CN107709320A

CN107709320A - A kind of pyrido nitrogen heterocyclic and its production and use

Info

Publication number: CN107709320A
Application number: CN201680031083.8A
Authority: CN
Inventors: 龙亚秋; 耿美玉; 许忠良; 艾菁
Original assignee: Shanghai Institute of Materia Medica of CAS
Current assignee: Shanghai Institute of Materia Medica of CAS
Priority date: 2015-05-21
Filing date: 2016-05-23
Publication date: 2018-02-16
Anticipated expiration: 2036-05-23
Also published as: US10710996B2; JP6621486B2; WO2016184434A1; CN107709320B; CN106279147A; JP2018520109A; EP3299369A1; EP3299369B1; EP3299369A4; US20180244667A1

Abstract

The invention discloses the pyrido nitrogen heterocyclic shown in a kind of below formula I, its isomers and pharmaceutically acceptable salt or pharmaceutically acceptable solvate, its preparation method and the composition for including the compound, and preparing the purposes in being used to treat the medicine of the disease relevant with protein kinase particularly c-Met such as tumor disease as Mutiple Targets kinases inhibitor.The tumour cell of the compound that formula I is represented expression high to c-Met kinases has efficient inhibitory activity, can effectively target the signal path of c-Met mediations, can be used in the overexpression of c-Met kinases caused by the relevant disease such as tumour treatment.

Description

A kind of pyrido nitrogen heterocyclic and its preparation method and application

Technical field

The present invention relates to field of medicinal chemistry, and in particular to a kind of pyrido nitrogen heterocyclic, its isomers and pharmaceutically acceptable salt or pharmaceutically acceptable solvate, preparation method and the composition comprising the compound.The invention further relates to the compound, its isomers and pharmaceutically acceptable salt and pharmaceutical compositions as multiple target point kinases inhibitor is preparing the purposes in the drug for treating the disease related with protein kinase especially c-Met such as tumor disease.

Background technique

The World Health Organization (WHO) claims in " global cancer report 2014 ", and global cancer patient is 14,000,000 people within 2012, it is contemplated that was incremented to 19,000,000 people by 2025, was up to 24,000,000 people by 2035.2012, newly-increased 3,070,000 cancer patients of China simultaneously caused about 2,200,000 people dead, accounted for the 21.9% and 26.8% of global total amount respectively.Just there is one to die of cancer in China, every five dieds.Cancer becomes the second largest killer for being only second to cardiovascular disease, seriously threatens the health of the mankind.In recent years the further investigation with people to oncobiology, receptor tyrosine kinase in tumorigenesis, drug resistance due to playing an important role, it has also become a kind of target spot of anti-tumor drug research and development.

C-Met is the important member of receptor tyrosine kinase family, there is high expression in the cancer and part sarcoma of the overwhelming majority and be closely related with poor prognosis, such as lung cancer, breast cancer, colon cancer, prostate cancer, pancreas cancer, gastric cancer, liver cancer, oophoroma, kidney, glioma, melanoma.For c-Met by interacting with its ligand HGF/SF or by intracellular section of other pathway activations of tyrosine kinase, induced cell proliferation, invasion, migration inhibit Apoptosis, promote angiogenesis, play an important role during the occurrence and development of tumour.Different from other kinases, c-Met can interact as the key node in tumor signal network path with other tumor-related molecules of cell surface, to be crosslinked activation amplification tumour correlation effect, be greatly promoted the generation, development and transfer of tumour.Studies have shown that Met gene magnification with 20% egf inhibitor (EGFR-TKIs) acquired resistance it is closely related；Met inhibitor and the drug combination of EGFR inhibitor can delay the generation of EGFR-TKIs acquired resistance, extend its clinical use service life.Therefore, targeting c-Met/HGF access becomes noticeable oncotherapy new strategy, and the anticancer drug research of the especially small molecule c-Met kinase inhibitor of the chemical block based on c-Met signal path becomes the research hotspot of current field of cancer treatment.Up to the present, existing 17 small molecule c-Met inhibitor enter or are carrying out clinical test, wherein ALK/c-Met dualkinase inhibitors of the PF-2341066 (Crizotinib) as high selectivity were approved by the fda in the United States for the treatment of the non-small cell lung cancer of the ALK fusion gene positive in 2011；XL184/BMS907351 is approved the treatment for medullary carcinoma of thyroid gland as the multiple kinase inhibitor such as Met, VEGFR-2 and RET, in the end of the year 2012.Although kinase inhibitor clinically shows excellent targeted therapy effect, drug resistance of tumor variation greatly reduces the effective of this kind of drug long-term treatment Property.Chemical structure it is similar but also the cross resistance problem of kinase inhibitor is got worse.On the other hand, although proving that specificity kinase inhibitor is better than multiple kinase inhibitor without positive evidence, the selectivity and undershooting-effect of kinases are closely related.Therefore, the emphasis direction of the anti-tumor drug research and development for being the discovery that targeting c-Met kinases at present of new construction new mechanism lead compound.

Summary of the invention

In order to solve the above-mentioned technical problem, it is an object of the present invention to provide a kind of pyrido nitrogen heterocyclic, its isomers, pharmaceutically acceptable salt or pharmaceutically acceptable solvates, and the pharmaceutical composition comprising the compound.

The purpose of another aspect of the present invention is to provide the preparation method of above compound.

The purpose of another aspect of the invention is to provide above compound in preparation for inhibiting the application in the active drug of tyrosine kinase c-Met, application in drug of the preparation for preventing or treating abnormal cell proliferation relevant to the intracorporal hepatocyte growth factor of biology and its receptor (c-Met), metamorphosis and the relevant disease of hypoerkinesia and disease relevant with angiogenesis or metastasis of cancer, in particular for the application in preparation prevention or treatment tumour growth and the drug of transfer.

In order to achieve the above-mentioned object of the invention, the present invention adopts the following technical scheme that:

One aspect of the present invention provides a kind of pyrido nitrogen heterocyclic, its isomers and pharmaceutically acceptable salt or pharmaceutically acceptable solvate, with structure shown in following general formula I:

Wherein,

Indicate singly-bound or double bond；

R¹And R²It is each independently selected from hydrogen and halogen；Preferably, R¹And R²It is each independently selected from hydrogen, F, Cl and Br；It is highly preferred that R¹Selected from hydrogen, Cl and Br；R²Selected from hydrogen, F and Cl；It is further preferred that R¹For hydrogen, Cl or Br；R₂For hydrogen or F；

There is no (for straight key) or X and Y to be each independently selected from C, N, O and S by X；Preferably, X is not present or X and Y is each independently selected from C, N and O；

N is 0,1,2 or 3；Preferably, 0,1 or 2 n；M is 0 or 1；

R³It is not present or for hydrogen, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₆-C₁₀Aryl, substituted or unsubstituted heteroatomic five yuan containing 1-2 in N, O, S or hexa-atomic saturation or unsaturated heterocycle group, substituted or unsubstituted heteroatomic five yuan containing 1-2 in N, O, S or hexa-atomic saturation or unsaturated heterocycle base carbonyl,Or substituted or unsubstituted heteroatomic five yuan or six-membered Hetero-aromatic group for containing 1-2 in N, O, S, wherein the substituent group for 1 or 2 and can be each independently selected from halogen ,-CN ,-CF₃、-NO₂, hydroxyl, C₁-C₆Alkyl, C₁-C₆Alkyl-substituted amido, C₁-C₆The C that alkoxy, benzyl, halogen replace₁-C₆Alkoxy, C₁-C₆Alkyl sulphonyl and unsubstituted or C₁-C₆Alkyl-substituted heteroatomic five yuan containing 1-2 in N and O or hexa-atomic saturation or unsaturated heterocycle base or heteroaryl ring group；It is highly preferred that R³It is not present or for hydrogen, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₆-C₁₀Aryl, substituted or unsubstituted heteroatomic five yuan containing 1-2 in N, O, S or hexa-atomic saturation or unsaturated heterocycle group, substituted or unsubstituted heteroatomic five yuan containing 1-2 in N, O, S or hexa-atomic saturation or unsaturated heterocycle base carbonyl,Or substituted or unsubstituted heteroatomic five yuan or six-membered Hetero-aromatic group for containing 1-2 in N and O, wherein the substituent group for 1 or 2 and can be each independently selected from halogen ,-CN, benzyl, C₁-C₆Alkyl, C₁-C₆Alkyl-substituted amido, C₁-C₆Alkyl sulphonyl and unsubstituted or C₁-C₆Alkyl-substituted heteroatomic five yuan containing 1-2 in N and O or hexa-atomic saturation or unsaturated heterocycle group；It is further preferred that R³It is not present or for hydrogen, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₆-C₁₀Aryl, substituted or unsubstituted heteroatomic five yuan containing 1-2 in N, O, S or hexa-atomic saturation or unsaturated heterocycle group, substituted or unsubstituted heteroatomic five yuan containing 1-2 in N, O, S or hexa-atomic saturation or unsaturated heterocycle base carbonyl,Or substituted or unsubstituted heteroatomic five yuan or six-membered Hetero-aromatic group for containing 1-2 in N and O, wherein the substituent group for 1 or 2 and can be each independently selected from halogen, benzyl, C₁-C₄Alkyl, C₁-C₄Alkyl-substituted amido, C₁-C₄Alkyl sulphonyl and unsubstituted or C₁-C₆Alkyl-substituted heteroatomic five yuan containing 1-2 in N and O or hexa-atomic saturation or unsaturated heterocycle group；Most preferably, R³It is not present or for C₁-C₃Alkyl, substituted or unsubstituted pyridyl group, substituted or unsubstituted morpholinyl, substituted or unsubstituted morpholinyl carbonyl,Generation or unsubstituted piperidyl, substituted or unsubstituted imidazole radicals, substituted or unsubstituted piperazinyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted pyrimidine radicals, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, Substituted or unsubstituted phenyl or substituted or unsubstituted pyrazolyl, wherein the substituent group can be 1 or 2 and be each independently selected from F, Cl, Br ,-NO₂、C₁-C₃Alkyl, benzyl, C₁-C₃Alkyl sulphonyl, C₁-C₃Alkyl-substituted amido, unsubstituted or C₁-C₆Alkyl-substituted piperidyl and morpholinyl；

R⁶It is not present or selected from hydrogen and C₁-C₆Alkyl；Preferably there is no or selected from hydrogen and C₁-C₄Alkyl；It is more preferably not present or selected from hydrogen and C₁-C₂Alkyl；It is most preferably not present or for hydrogen or methyl；

R⁷It is not present or selected from hydrogen and C₁-C₆Alkyl；Preferably there is no or for hydrogen, methyl, ethyl or propyl；It is most preferably not present or for methyl；

Z is amino, phenylacetyl amido or following any structure:

In above-mentioned general formula II, III, IV, V, R⁴Selected from hydrogen, C₁-C₆Alkyl and C₅-C₁₀Aryl or heteroaryl；Preferably, R⁴Selected from hydrogen and C₁-C₆Alkyl；It is highly preferred that R⁴Selected from hydrogen and C₁-C₃Alkyl；Most preferably, R⁴For hydrogen or methyl；R⁵And R^5’It is each independently selected from hydrogen, halogen and C₁-C₆Alkoxy；Preferably, R⁵And R^5’It is each independently selected from hydrogen, F, Cl, Br and C₁-C₄Alkoxy；It is highly preferred that R⁵And R^5’It is each independently selected from hydrogen, F and C₁-C₂Alkoxy；

Most preferably, Z is amino, phenylacetyl amido or following any structure:

Ring B is containing 1 or 2 heteroatomic five yuan in N, O, S or hexa-atomic saturation or unsaturated heterocycle group or miscellaneous aromatic group；Preferably, ring B is containing 1 or 2 heteroatomic five yuan in N or O or hexa-atomic saturation or unsaturated heterocycle group or miscellaneous aromatic group；It is highly preferred that ring B is five yuan containing 1 or 2 N atom or hexa-atomic saturation or unsaturated heterocycle group or miscellaneous aromatic group；Most preferably, ring B is with pyridine or together with X-shaped at structure shown in one of following skeleton symbol:

Wherein, halogen includes F, Cl, Br, I；

Most preferably, the compound is selected from one of following compounds compound:

Another aspect of the present invention provides the preparation method of pyrido nitrogen heterocyclic shown in a kind of above-mentioned general formula I, its isomers, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate, and this method is as shown in one of following reaction scheme:

Reaction scheme one:

Wherein, R⁸ForR⁹ForY、R²、R³、R⁷, Z, m and n define it is identical as the definition in above-mentioned general formula I；

(1) compound 5 is obtained by compound 4 through chlorination, and chlorinating agent is thionyl chloride (SOCl₂)/N, N- dimethyl ammonium formate (DMF), phosphorus oxychloride (POCl₃)/DMF or POCl₃/ n,N-diisopropylethylamine (DIEA)/acetonitrile (MeCN) etc., preferably POCl₃/DMF。

(2) compound 6 is obtained by the deprotection of compound 5.Deprotect reagent are as follows: Boron tribromide (BBr₃)/methylene chloride (DCM), 40% hydrogen bromide (HBr) aqueous solution, pyridine hydrochloride, hydrochloric acid or sulfuric acid, hydrochloric acid-aluminium chloride, aluminium chloride-ethyl mercaptan, trim,ethylchlorosilane (TMSCl)/sodium iodide (NaI), trifluoromethanesulfonic acid.Preferably trifluoromethanesulfonic acid.(3) compound 6 is reacted through Mitsunobu generates compound 7, and selected reagent is diethyl azodiformate (DEAD)/triphenylphosphine (PPh₃), N ',-three fourth phosphine TBP of N '-tetra isopropyl azodicarboxy amide (TIPA), 1,1 '-(azo-2-carboxylic acid) two piperidines (ADDP)-TBP, tetramethyl azoformic acid ammonium (TMAD)-TBP, 4,7- dimethyl -3,4,5,6,7,8- hexahydro -1,2,4,7- tetra- azepine Xin Yin -3,8- diketone (DHTD)-TBP, cyanomethylene tri-n-butyl phosphine (CMBP) or cyanomethylene trimethyl-phosphine (CMMP).Preferably DEAD/PPh₃。

(4) 7 nucleo philic substitution reaction of compound generates compound 8, and selected reagent is common organic base or inorganic base, such as Anhydrous potassium carbonate, cesium carbonate, triethylamine (TEA), DIEA, potassium tert-butoxide, sodium hydride, sodium methoxide, sodium ethoxide；Preferably Anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium tert-butoxide.

(5) compound 8 obtains compound 9, preferred reaction conditions through debrominate are as follows: palladium carbon Pd/C- ammonium formate, Pd/C- acetamide, Pd/C- hydrogen；Preferably Pd/C- ammonium formate.

Reaction scheme two:

(1) 5 debrominate of compound obtains compound 10, preferred reaction conditions are as follows: Pd/C- ammonium formate, Pd/C- acetamide, Pd/C- hydrogen；Preferably Pd/C- ammonium formate.

(2) compound 11 is obtained by the deprotection of compound 10.Deprotect reagent are as follows: BBr₃/ DCM, 40%HBr aqueous solution, pyridine hydrochloride, hydrochloric acid or sulfuric acid, hydrochloric acid-aluminium chloride, aluminium chloride-ethyl mercaptan, TMSCl/NaI, trifluoromethanesulfonic acid.Preferably trifluoromethanesulfonic acid.

(3) compound 11 is reacted through Mitsunobu generates compound 12, and selected reagent is DEAD/PPh₃, TIPA-TBP, ADDP-TBP, TMAD-TBP, DHTD-TBP, CMBP or CMMP.Preferably DEAD/PPh₃。

(4) 12 nucleo philic substitution reaction of compound generates compound 9, and selected reagent is common organic base or inorganic base, such as Anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium tert-butoxide, sodium hydride, sodium methoxide, sodium ethoxide；Preferably Anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium tert-butoxide.

Reaction scheme three:

Wherein, R¹⁰ForR⁹ForX、Y、R²、R³、R⁶、R⁷, the definition of Z, m and n it is identical as claim 1-5 respectively；X ' is Cl or Br；

(1) compound 14 is dechlorinated obtains compound 15, and reaction reagent is zinc (Zn)/acetic acid (MeCOOH)；

(2) compound 16 obtains compound 17, chlorinating agent SOCl through chlorination₂/DMF、POCl₃/DMF、POCl₃/ DIEA/MeCN etc., preferably POCl₃/DIEA/MeCN；

(3) 17 nucleo philic substitution reaction of compound generates compound 18, and selected reagent is common organic base or inorganic base, such as Anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium tert-butoxide, sodium hydride, sodium methoxide, sodium ethoxide；Preferably Anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium tert-butoxide；

Reaction scheme four:

(1) compound 15 obtains compound 15I, chlorinating agent SOCl through chlorination₂/DMF、POCl₃/DMF、POCl₃/ DIEA/MeCN etc., preferably POCl₃/DIEA/MeCN；

(2) compound 15I nucleo philic substitution reaction generates compound 15II, and selected reagent is common organic base or inorganic base, such as Anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium tert-butoxide, sodium hydride, sodium methoxide, sodium ethoxide；Preferably Anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium tert-butoxide；

(3) compound 15II generates compound 18 through Suzuki coupling reaction, and alkali used is potassium acetate, potassium phosphate or potassium carbonate；Solvent for use is dimethyl sulfoxide, DMF, dioxane or toluene, and suitable water is added；Catalyst used is tetra-triphenylphosphine palladium, 1,1 '-bis- Diphenyl phosphino ferrocene palladium chloride PdCl₂(dppf)；

Reaction scheme five:

Wherein, R¹⁰ForR⁹ForX、Y、R²、R³、R⁶、R⁷, the definition of Z, m and n it is identical as claim 1-5 respectively；

(1) substitution reaction generates compound 19, and selected reagent is common organic base or inorganic base, such as Anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium tert-butoxide, sodium hydride, sodium methoxide, sodium ethoxide；Preferably Anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium tert-butoxide；

(2) compound 19 obtains compound 20 through reduction, and go back original reagent used is nickel chloride (NiCl₂)/sodium borohydride (NaBH₄)、Zn/AcOH、Pd/C-H₂, Fe/ hydrogen chloride (HCl), vulcanized sodium (Na₂S)/ethyl alcohol (EtOH), ammonium hydro sulfide (NH₄HS), lithium aluminium hydride reduction (LiAlH₄)；Preferably NiCl₂/NaBH₄、Pd/C-H₂；

(3) compound 20 obtains compound 21 and 22 through cyclization, and cyclization condition is aldehyde radical ethyl acetate, and solvent is various Conventional solvents, such as methanol (MeOH), EtOH, acetonitrile (MeCN), dioxane etc.；

(4) chlorination, chlorinating agent SOCl₂/DMF、POCl₃/DMF、POCl₃/ DIEA/MeCN etc., preferably POCl₃/DIEA/MeCN；

(5) nucleophilic substitution, selected reagent are common organic base or inorganic base, such as Anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium tert-butoxide, sodium hydride, sodium methoxide, sodium ethoxide；Preferably Anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium tert-butoxide.

Another aspect of the present invention also provides a kind of composition selected from compound, its isomers shown in one or more general formula I, pharmaceutically acceptable salt or pharmaceutically acceptable solvate comprising therapeutically effective amount.

Another aspect of the present invention also provides compound shown in general formula I, its isomers, pharmaceutically acceptable salt, pharmaceutically acceptable solvate and combinations thereof and is preparing the application in the drug as multiple target point kinases inhibitor, uses in preparation Application in the inhibition active drug of tyrosine kinase c-Met, application in drug of the preparation for preventing or treating abnormal cell proliferation relevant to biological intracorporal hepatocyte growth factor receptor (c-Met), metamorphosis and the relevant disease of hypoerkinesia and disease relevant with angiogenesis or metastases, the especially application in preparation prevention or treatment tumour growth and the drug of transfer.

The kinases includes c-Met, Flt-1, PDGFR- α, PDGFR- β, RET, c-Src, EPH-A2, FGFR, Abl, Lck, KDR, IGF-1 α and ALK.

The drug is for treating and/or preventing disease related with protein kinase especially c-Met, such as tumour.

In the present invention, the tumour is lung cancer, thyroid gland encephaloid, glioblastoma, gastric cancer, clear-cell carcinoma, breast cancer, oophoroma, prostate cancer or colorectal cancer.

The method have the advantages that:

By screening to c-Met kinase activity, inventor's discovery: the compound that above-mentioned general formula I is indicated has efficient inhibitory activity to c-Met kinases at 10nM；There is efficient inhibitory activity to the highly expressed tumour cell of c-Met kinases at 100nM.Representative compound 7S shows good medicine for property: bioavilability F=51.8%, mean residence time MRT=2.6h, half-life period t_1/2=1.66h, area AUC=16652h*ng/ml when medicine.And, the micromolecular inhibitor animal interior curative effect is good: once a day oral administration, 100mg/kg group successive administration 21 days, it is 9.5% to human lung cancer EBC-1 nude mouse subcutaneous transplantation tumor Relative tumor proliferation rate T/C, gross tumor volume growth inhibition rate GI is 96.5%, tumor-like hyperplasia is 86.9%, safe and non-toxic in effective dose.Therefore, the compound that general formula I is indicated can effectively target the signal path of c-Met mediation, can be used in the treatment of the related diseases such as tumour caused by over-expressing with c-Met kinases.The pharmaceutical composition of the compound indicated containing general formula I allowed on galenic pharmacy can equally play the signal path that effective targeting c-Met is mediated, and can be used in the treatment of the related diseases such as tumour caused by over-expressing with c-Met kinases.

Detailed description of the invention

Fig. 1 shows that compound 7S acts on the experimental therapy of human lung cancer EBC-1 Nude Mice.

Specific embodiment

Embodiment:

The present invention will be further described below with reference to examples, but does not limit the scope of the invention.

Compound¹The measurement of H-NMR spectroscopic data uses Varian Mercury-300MHz or Varian Mercury-400MHz nuclear magnetic resonance, mass spectrum EI-MS 95 mass spectrograph of Finnigan MAT, and ESI-MS is measured using Finnigan LCQ Deca mass spectrograph.Rapid column chromatography carries out on silica gel H (10-40 μM).Reagent purification is referring to Purification of laboratory Chemicals；D.D.Perrin；W.L.F.Armarego and D.R.Perrin Eds., Pergamon Press:Oxiford, 1980.

It is such as not specifically noted, the reagent and method that reagent of the present invention and method etc. are well known in the art.

The synthesis of 1 segment II series of embodiment

2011/137342 A1 of this segment synthesized reference WO

1- (methoxycarbonyl) cyclopropane monocarboxylic acid (23)

Cyclopropane dicarboxylic acid's dimethyl ester (10.12g, 63.99mmol) is dissolved in 100mL (1: 1V: V) CH₃OH/H₂It in O, stirs at room temperature, weighs (2.68g, 63.99mmol) lithium hydroxide and be dissolved in 20ml H₂It in O, is slowly added into above-mentioned solution in three times at room temperature, continues to be stirred to react 1h after adding, adjusted pH value with dilute hydrochloric acid after the reaction was completed and extracted to 3, DCM, anhydrous sodium sulfate is dry, continues to react in next step without further purification.

1- ((4- fluorophenyl) carbamyl) cyclopropane monocarboxylic acid (25)

By (9.21g, 63.99mmol) compound 23, (12.15ml, 127.98mmol) para-fluoroaniline is dissolved in 150ml DCM, (12.97g is added at room temperature, 95.98mmol) HOBt (hydroxybenzotriazole), (14.90g, 95.98mmol) 1- (3- dimethylamino-propyl) -3- ethyl carbodiimide (EDC), it is stirred at room temperature, TLC tracking reaction, most DCM is boiled off after the reaction was completed, EA extraction is added, is saturated NaHCO₃It washes, the washing of pH=3, saturated brine washing adds anhydrous Na₂SO₄It is dry, it is concentrated to get 24 crude product of compound.Obtained crude product is directly dissolved in 100mL (1: 1V: V) MeOH/H₂In O, stir at room temperature, it is rear that (3.06g, 127.98mmol) lithium hydroxide is added, continue to be stirred to react 1h after adding, TLC tracking reaction adjusts pH value to 3 with dilute hydrochloric acid after the reaction was completed, that is, a large amount of solids are precipitated, filtering, dry pale solid 10.56g, two step yields 74.1%.¹H NMR(CDCl₃, 300MHz): δ 7.57-7.53 (m, 2H), 7.05-7.00 (m, 2H), 1.46-1.43 (m, 2H), 1.40-1.37 (m, 2H).

N- (the fluoro- 4- hydroxy phenyl of 3-)-N- (4- fluorophenyl) cyclopropane -1,1- diamides (26)

By (2.00g, 8.97mmol) compound 25, (1.14g, 8.97mmol) 4- amino -2- fluorophenol are dissolved in 10ml DCM, and (1.21g is added at room temperature, 13.46mmol) HOBt, (1.77g, 13.46mmol) EDC, is stirred at room temperature, TLC tracking reaction, most DCM is boiled off after the reaction was completed, and EA extraction is added, is saturated NaHCO₃It washes, the water of pH=3 It washes, saturated brine washing adds anhydrous Na₂SO₄It is dry, it is concentrated to get crude product, methanol crystallization obtains Tan solid 63%.¹H NMR (DMSO, 400MHz): δ 10.51 (s, 1H), 10.32 (s, 1H), 10.00 (s, 1H), 7.77 (d, J=12.9Hz, 1H), 7.66-7.61 (m, 2H), 7.41 (d, J=8.7Hz, 1H), 7.30 (t, J=8.8Hz, 1H), 7.15 (d, J=9.0Hz, 2H), 1.61 (m, 2H), 1.44 (m, 2H)

N- (the fluoro- 4- hydroxy phenyl of 3-)-N- (4- fluorophenyl)-N- methyl cyclopropane -1,1- diamides (27)

With compound 26, initial feed is to fluoro- methylphenylamine for the preparation of compound 27；¹H NMR (DMSO, 300MHz): δ 9.56 (s, 1H), 9.42 (s, 1H), 7.35-7.23 (m, 2H), 7.19-7.03 (m, 2H), 6.97-6.87 (m, 1H), 6.85-6.75 (m, 1H), 3.22 (s, 3H), (1.38-1.10 m, 4H)

N- (3,4- difluorophenyl)-N- (the fluoro- 4- hydroxy phenyl of 3-) cyclopropane -1,1- diamides (28)

The preparation of compound 28 is the same as compound 26, initial feed 3,4- difluoroaniline；¹H NMR(CDCl₃, 300MHz): δ 10.64 (s, 1H), 7.72-7.58 (m, 1H), 7.13-7.00 (m, 2H), 6.83 (t, J=8.5Hz, 1H), 6.52-6.34 (m, 2H), 1.97 (m, 2H)

N- (the fluoro- 3- methoxyl group of 4-)-N- (the fluoro- 4- hydroxy phenyl of 3-) cyclopropane -1,1- diamides (29)

With compound 26, initial feed is the fluoro- 3- aminoanisole of 4- for the preparation of compound 29；¹H NMR (DMSO, 400MHz): δ 10.08 (s, 1H), 9.87 (s, 1H), 9.62 (s, 1H), 7.57-7.48 (m, 2H), 7.21-7.11 (m, 3H), 6.87 (t, J=9.2Hz, 1H), 3.80 (s, 3H), 1.50-1.37 (m, 4H)

N- (4- fluorophenyl)-N- (4- hydroxy phenyl) cyclopropane -1,1- diamides (31)

(0.50g, 2.24mmol) compound 25 is added in round-bottomed flask, 2ml SOCl is added₂, 80 DEG C of reaction 2h, after be concentrated to give 30 crude product of compound, by concentrate with 5ml DCM dilute；Weigh (366mg, 3.36mmol) para hydroxybenzene amine dissolves in 30ml DCM, (386mg is added, 3.36mmol) DIEA, compound 30 is slowly added drop-wise in reaction solution under ice bath, it is added dropwise to move back to room temperature and continues to be stirred to react 1h, EA extraction is added after the reaction was completed, is saturated NaHCO₃It washes, the washing of pH=3, saturated brine washing adds anhydrous Na₂SO₄It is dry, it is concentrated to get crude product, column chromatographs to obtain khaki solid chemical compound 31, two step yields 63%.¹H NMR (DMSO, 300MHz): δ 10.18 (s, 1H), 9.74 (s, 1H), 9.25 (s, 1H), 7.63 (dd, J=8.1,5.2Hz, 2H), 7.36 (d, J=8.2Hz, 2H), 7.15 (t, J=8.4Hz, 2H), 6.70 (d, J=7.9Hz, 2H), 1.47-1.41 (m, 2H), 1.14-1.06 (m, 2H)

N- (4- aminophenyl)-N- (4- hydroxy phenyl) cyclopropane -1,1- diamides (32)

With compound 31, initial feed is to Isosorbide-5-Nitrae-phenylenediamine, two step yields 56% for the preparation of compound 32.¹H NMR (DMSO, 300MHz): δ 10.25 (s, 1H), 9.57 (s, 1H), 7.68-7.60 (m, 2H), 7.30-7.10 (m, 4H), 6.51 (d, J=8.6Hz, 2H), 4.96 (s, 2H), 1.53-1.37 (m, 4H)

The synthesis of 2 segment III of embodiment

1- (4- fluorophenyl) -2- oxo -1,2- dihydropyridine -3- formic acid (34)

By (300mg, 1.95mmol) 2- oxo -2H- pyrans -3- methyl formate, (0.19ml, 1.96mmol) para-fluoroaniline is dissolved in 5ml DMF, and after being stirred to react 6h at room temperature, (0.49g is added in backward reaction solution, 2.54mmol) EDC, (60mg, 0.49mmol) DMAP (dimethyl aminopyridine) is stirred to react overnight, after the reaction was completed at room temperature, EA extraction is added, is saturated NaHCO₃It washes, saturated brine washing adds anhydrous Na₂SO₄It is dry, it is concentrated to get crude product.Obtained crude product is directly dissolved in the THF/H of the NaOH of 20mL 2N₂In O (1: 1V: V), 65 DEG C are stirred to react 2h, adjust pH value to 1 with dilute hydrochloric acid after the reaction was completed, that is, a large amount of solids are precipitated, filter, dry khaki solid chemical compound 34.¹H NMR (DMSO, 300MHz): δ 8.47 (dd, J=7.1,2.2Hz, 1H), 8.19 (dd, J=6.6,2.2Hz, 1H), 7.59-7.63 (m, 2H), 7.39-7.44 (m, 2H), 6.78 (dd, J=6.6,7.1Hz, 1H)

N- (the fluoro- 4- hydroxy phenyl of 3-) -1- (4- fluorophenyl) -2- oxo -1,2- dihydropyridine -3- carbamide (36)

(0.52g, 2.24mmol) compound 34 is added in round-bottomed flask, 2ml SOCl is added₂, 80 DEG C of reaction 2h, after be concentrated to give compound 35, by concentrate with 5ml DCM dilute；Weigh (427mg, 3.36mmol) the fluoro- aniline of hydroxyl -3 is dissolved in 30ml DCM, (386mg is added, 3.36mmol) DIEA, compound 35 is slowly added drop-wise in reaction solution under ice bath, it is added dropwise to move back to room temperature and continues to be stirred to react 1h, EA extraction is added after the reaction was completed, is saturated NaHCO₃It washes, saturated brine washing adds anhydrous Na₂SO₄It is dry, it is concentrated to get crude product, column chromatographs to obtain khaki solid chemical compound 36, two step yields 52%.¹H NMR (DMSO, 300MHz): δ 11.79 (s, 1H), 9.72 (s, 1H), 8.55 (d, J=7.2Hz, 1H), 8.11 (dd, J=13.6,6.3Hz, 1H), 7.74 (d, J=13.5Hz, 1H), 7.59 (dt, J=13.0,6.5Hz, 2H), 7.41 (dd, J=16.3,7.6Hz, 2H), 7.20-7.09 (m, 1H), 6.92 (t, J=9.2Hz, 1H), 6.72 (dd, J=14.6,7.3Hz, 1H)

The synthesis of 3 segment IV of embodiment

4- (benzyloxy) -3- fluoroaniline (37)

It will be to hydroxyl -3- fluoroaniline (1.0g, it 7.87mmol) is dissolved in 10mL anhydrous DMF, it is cooled to 0 DEG C, (0.88g, 7.87mmol) potassium tert-butoxide is added, after stirring 10min, (1.35g, 7.87mmol) benzyl bromine, TLC tracking is added, EA extraction is added after the reaction was completed, is saturated NaHCO₃It washes, saturated brine washing adds anhydrous Na₂SO₄It is dry, it is concentrated to get 37 crude product of compound, column chromatographs to obtain colourless liquid, yield 52%.¹H NMR(CDCl₃, 300MHz): δ 7.41-7.28 (m, 5H), 6.91 (dd, 1H), 6.46 (dd, 1H), 6.32 (m, 1H), 4.97 (s, 2H), 4.98 (s, 2H)

1- (4- (benzyl oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) -2- oxo -1,2- dihydropyridine -3- carbamide (41)

With 36, initial feed is 4- (benzyloxy) -3- fluoroaniline (37) for the synthesis of compound 41.¹H NMR (DMSO, 300MHz): δ 11.93 (s, 1H), 8.56 (dd, J=7.2,1.9Hz, 1H), 8.10 (dd, J=6.6,1.9Hz, 1H), 7.79-7.70 (m, 2H), 7.65-7.37 (m, 7H), 7.37-7.27 (m, 1H), 7.20 (t, J=8.8Hz, 2H), 6.70 (t, J=7.0 Hz, 1H), 5.30 (s, 2H)

1- (the fluoro- 4- hydroxy phenyl of 3-)-N- (4- fluorophenyl) -2- oxo -1,2- dihydropyridine -3- carbamide (42)

Above-mentioned (432mg, 1mmol) compound 41 is dissolved in 3ml trifluoroacetic acid, it is rear to instill 100 μ l trifluoromethanesulfonic acids, it is stirred to react, TLC tracking, addition EA is rushed dilute after the reaction was completed, adjusts pH=6 with the NaOH of 2N, EA extraction, saturated brine washing, adds anhydrous Na₂SO₄It is dry, it is concentrated to get 42 crude product of compound, column chromatographs to obtain faint yellow solid, yield 87%.¹H NMR (DMSO, 300MHz): δ 11.96 (s, 1H), 10.40 (s, 1H), 8.55 (dd, J=7.3,2.1Hz, 1H), 8.08 (dd, J=6.6,2.1Hz, 1H), 7.73 (dd, J=8.9,5.0Hz, 2H), 7.47 (dd, J=11.8,2.3Hz, 1H), 7.26-7.03 (m, 4H), 6.69 (t, J=6.9Hz, 1H)

The synthesis of 4 segment V of embodiment

This segment synthesized reference J Med Chem, 2008,51,5330-5341

3- oxo -4- ethyl phenylbutyrate (44)

It weighs (2g, 13.9mmol) malonic acid ring (Asia) isopropyl ester to be dissolved in 40ml methylene chloride, (1.65g is added, 20.9mmol) pyridine, be cooled to 0 DEG C, after slowly be added dropwise (2.14g, 13.9mmol) phenyllacetyl chloride, continue to be stirred to react 3h at 0 DEG C, 100mlDCM is added after the completion and rushes dilute, the HCl of addition 50ml 1N, stirring, separate organic phase, anhydrous Na₂SO₄It is dry, it is concentrated to get crude product.Crude product is directly added into 50ml EtOH, is refluxed overnight, concentration rear pillar chromatographs give light yellow oil, two-step reaction yield 44%.¹H NMR(CDCl₃, 300MHz): δ 7.42-7.14 (m, 5H), 4.15 (q, J=7.1Hz, 2H), 3.81 (s, 2H), 3.43 (s, 2H), 1.24 (t, J=7.2Hz, 3H)

4- (dimethylamino) -2- ((dimethylamino) methylene) -3- oxo -4- ethyl phenylbutyrate (45)

Aforesaid liquid is added in DMF-DMA, 3h is stirred to react at 110 DEG C, is concentrated after the reaction was completed, EA is added and stirs to obtain white solid, yield 81%.¹H NMR (DMSO, 300MHz): δ 7.37-7.14 (m, 5H), 7.06 (s, 1H), 7.04 (s, 1H), 4.07-3.87 (m, 2H), 2.92 (s, 6H), 2.65 (s, 6H), 1.13 (t, J=7.1Hz, 3H)

4- oxo -5- phenyl-Isosorbide-5-Nitrae-dihydropyridine -3- Ethyl formate (46)

Above-mentioned solid is dissolved in EtOH, the NH of 3eq is added₄Cl, flow back 2h, after be cooled to room temperature, filtration drying obtains faint yellow solid, yield 76%.¹H NMR (DMSO, 300MHz): δ 8.22 (s, 1H), 7.86 (s, 1H), 7.64-7.56 (m, 2H), 7.47-7.25 (m, 3H), 4.21 (q, J=7.1Hz, 2H), 1.27 (t, J=7.1Hz, 3H)

4- oxo -5- phenyl-Isosorbide-5-Nitrae-dihydropyridine -3- formic acid (47)

Above-mentioned solid is dissolved in ethyl alcohol, the NaOH of 2N is added, 70 DEG C are stirred to react 2h, cool down after the completion, and the HCl of 1.5N is added, and obtain solid, filtration drying, yield 90%.¹H NMR (DMSO, 300MHz): δ 13.21 (s, 1H), 8.62 (s, 1H), 8.25 (s, 1H), 7.75-7.62 (m, 2H), 7.53-7.36 (m, 3H)

5- (4- fluorophenyl) -4- oxo-Isosorbide-5-Nitrae-dihydropyridine -3- formic acid (48)

With 47, initial feed is to fluorophenylacetyl chloride for the synthesis of compound 48.¹(t, J=8.9Hz, the 2H) of H NMR (DMSO, 300MHz): δ 13.21 (s, 1H), 8.63 (s, 1H), 8.27 (s, 1H), 7.73 (dd, J=8.7,5.7Hz, 2H), 7.29

The synthesis of 5 N- of embodiment (4- ((chloro- 1, the 6- benzodiazine -4- alkyl of 7-) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (1S)

5- (methoxymethylene) -2,2- dimethyl-1,3-dioxane -4,6- diketone (49)

10g Michaelis acid is added in 40ml orthocarbonic acid trimethyl, 100 DEG C are stirred to react 3h, cool down after the reaction was completed, and ultrasonic obtain of petroleum ether is added and largely precipitates, filters, PE rinses to obtain product, is directly used in next step without purifying.

5,7- bis- chloro- 1,6- naphthyridines -4 (1H) -one (51)

The chloro- 4-aminopyridine of 2,6- bis- of 1g, 6.13mmol are dissolved in isopropanol, it is rear that 2eq compound 49, rear liter is added Temperature is stirred to react after 1h to 110 DEG C and a large amount of solids is precipitated, and continues to be stirred to react 2h, after be cooled to room temperature, washed with isopropanol, ether washes to obtain product, yield 96%；

Compound obtained above is suspended in 10ml/g in diphenyl ether, be warming up to 220 DEG C be stirred to react 1h after a large amount of solids are precipitated, be cooled to room temperature, a large amount of PE washing be added, filters to obtain product, yield 94%.¹H NMR (300MHz, DMSO) δ 12.11 (s, 1H), 7.93 (dd, J=7.7,5.5Hz, 1H), 7.48 (s, 1H), 6.17 (d, J=7.5Hz, 1H)

Chloro- 1,6- naphthyridines -4 (1H) -one (52) of 7-

The processing of zinc: weighing a certain amount of zinc powder and dilute hydrochloric acid be added, and the amount that dilute hydrochloric acid is added is that zinc powder is made slowly to emerge bubble, stirs 30min at room temperature, to remove the oxide layer of zinc surface, after water is outwelled, be washed with water twice, acetone is washed twice, and ether is washed twice, and decompressing and extracting is spare.

The compound 51 of 1eq is dissolved in dry MeOH solution, the rear zinc powder that 4eq is added, the acetic acid of 10eq is added in stirring at room temperature, after be brought rapidly up to 70 DEG C, TLC tracking filters after the reaction was completed, the solid of water ultrasound is added after concentration, filters, 1: 1 EtOH/Et₂O washs to obtain target compound, yield 74%；¹H NMR (300MHz, DMSO) δ 8.99 (s, 1H), 8.00 (d, J=7.6Hz, 1H), 7.49 (s, 1H), 6.17 (d, J=7.6Hz, 1H)

4,7- bis- chloro- 1,6- naphthyridines (53)

The compound 52 of (340mg, 1.89mmol) is dissolved in 1,2- dichloroethanes, (653 μ l are added, 3.95mmol) DIEA stirs lower instillation (345 μ l, 3.78mmol) phosphorus oxychloride, 70 DEG C are stirred to react 30min, be cooled to room temperature, after pour into ice water, adjust pH to 8 with the NaOH of 2N, EA extraction, the NH of saturation₄The washing of Cl solution, saturation NaCl washing, anhydrous Na₂SO₄It is dry, it is concentrated under reduced pressure, column chromatographs to obtain target compound, yield 94%；¹H NMR (300MHz, DMSO) δ 9.47 (d, J=0.6Hz, 1H), 9.10 (d, J=4.7Hz, 1H), 8.18 (s, 1H), 7.94 (d, J=4.8Hz, 1H)

N- (4- ((chloro- 1, the 6- benzodiazine -4- alkyl of 7-) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (1S)

The compound 53 of (0.2g, 1mmol) is dissolved in anhydrous DMF, the phenol of 1.1eq is added, it is rear that 1.1eq potassium tert-butoxide is added, use N₂Three times, 110 DEG C are stirred to react for displacement, and TLC tracking, addition EA is rushed dilute after the reaction was completed, with the NH of saturation₄The washing of Cl solution, saturation NaCl washing, anhydrous Na₂SO₄It is dry, it is concentrated under reduced pressure, column chromatographs to obtain target compound, yield 76%；¹H NMR (300MHz, DMSO) δ 10.77 (s, 1H), 9.92 (s, 1H), 9.57 (d, J=0.7Hz, 1H), 8.95 (d, J=5.3Hz, 1H), 8.23-8.04 (m, 2H), 7.62 (dd, J=9.2,5.1Hz, 2H), 7.51 (dd, J=11.2,2.6Hz, 1H), 7.36-7.13 (m, 3H), 6.82 (d, J=5.3Hz, 1H), 1.68-1.52 (m, 4H)

The synthesis of 6 N- of embodiment (4- ((7- dimethylamino -1,6- benzodiazine -4- alkyl) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (2S)

7- (dimethylamino) -1,6- naphthyridines -4 (1H) -one (54)

The compound 52 of 1eq is dissolved in dry DMF solution, the rear potassium tert-butoxide (t-BuOK) that 2eq is added is warming up to 110 DEG C and is stirred to react, and TLC tracking, addition EA is rushed dilute after the reaction was completed, with the NH of saturation₄The washing of Cl solution, saturation NaCl washing, anhydrous Na₂SO₄It is dry, it is concentrated under reduced pressure, column chromatographs to obtain target compound；¹H NMR (400MHz, DMSO) δ 11.28 (s, 1H), 8.80 (s, 1H), 7.70 (dd, J=7.5,5.8Hz, 1H), 6.22 (s, 1H), 5.82 (d, J=7.6Hz, 1H), 3.08 (s, 6H)

Chloro- 1, the 6- naphthyridines -7- dimethylamine (55) of 4-

The compound 54 of 1eq is dissolved in 1,2- dichloroethane solution, the rear DIEA that 3eq is added, the phosphorus oxychloride of 2eq is warming up to 70 DEG C and is stirred to react, and TLC tracking, addition EA is rushed dilute after the reaction was completed, with the NH of saturation₄The washing of Cl solution, saturation NaCl washing, anhydrous Na₂SO₄It is dry, it is concentrated under reduced pressure, column chromatographs to obtain target compound；¹H NMR (300MHz, CDCl3) δ 9.23 (s, 1H), 8.63 (d, J=4.7Hz, 1H), 7.07 (d, J=4.7Hz, 1H), 6.80 (s, 1H), 3.20 (d, J=0.9Hz, 6H)

N- (4- ((7- dimethylamino -1,6- benzodiazine -4- alkyl) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (2S)

The compound 55 of (0.2g, 0.97mmol) is dissolved in anhydrous DMF, the phenol of 1.1eq is added, it is rear that 1.1eq potassium tert-butoxide is added, use N₂Three times, 110 DEG C are stirred to react for displacement, and TLC tracking, addition EA is rushed dilute after the reaction was completed, with the NH of saturation₄The washing of Cl solution, saturation NaCl washing, anhydrous Na₂SO₄It is dry, it is concentrated under reduced pressure, column chromatographs to obtain target compound, yield 81%.¹H NMR (300MHz, CDCl₃) δ 7.74-7.61 (m, 1H), 7.43-7.29 (m, 2H), 7.14-7.05 (m, 1H), 7.05-6.95 (m, 1H), 6.95-6.82 (m, 2H), 6.72-6.64 (m, 1H), 6.63-6.53 (m, 1H), 6.38 (d, J=2.4Hz, 1H), 6.20 (d, J=2.3Hz, 1H), 3.25 (s, 6H), 1.49 (m, 4H)；EI MS m/z 503[M]⁺.

The synthesis of 7 N- of embodiment (4- ((7- methoxyl group -1,6- benzodiazine -4- alkyl) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (3S)

The bromo- 2- methoxyl group of 3- -4-aminopyridine (56)

2- methoxyl group-the 4-aminopyridine of (5g, 40.3mmol) is dissolved in MeCN, (7.18g is added portionwise at 0 DEG C, NBS 40.3mmol), after slowly return to reaction be stirred at room temperature, TLC tracking, addition EA is rushed dilute after the reaction was completed, with the NH of saturation₄The washing of Cl solution, sodium hydrosulfite washing, saturation NaCl washing, anhydrous Na₂SO₄It is dry, it is concentrated under reduced pressure, column chromatographs to obtain target compound, yield 77%.¹H NMR (300MHz, CDCl₃) (s, the 3H) of δ 7.57 (d, 1H), 6.36 (d, 1H), 6.20 (s, 2H), 3.7

7- methoxyl group -1,6- naphthyridines -4 (1H) -one (59)

The bromo- 2- methoxyl group -4-aminopyridine of the 3- of 1eq is dissolved in isopropanol, it is rear that 2eq compound 49 is added, after be warming up to 110 DEG C be stirred to react 1h after a large amount of solids are precipitated, be cooled to room temperature after 2h, washed with isopropanol, ether washes to obtain product Compound 57, yield 92%；

Compound obtained above is suspended in 10ml/g in diphenyl ether, be warming up to 220 DEG C be stirred to react 1h after a large amount of solids are precipitated, be cooled to room temperature, the washing of bulk petroleum ether be added, filters to obtain product Compound 58, yield 96%.

Above-mentioned solid is dissolved in methanol, the ammonium formate of 2eq is added, the rear 10%Pd/C that 10% weight is added is stirred to react at 60 DEG C, TLC tracking, after the reaction was completed, cold filtration, filtrate concentration, after extracted with EA, saturation and NaCl washing, anhydrous Na₂SO₄It is dry, compound 59 is concentrated under reduced pressure to obtain.¹H NMR (400MHz, DMSO) δ 8.89 (s, 1H), 8.46 (s, 1H), 7.87 (d, J=7.6Hz, 1H), 6.75 (s, 1H), 5.97 (d, J=7.6Hz, 1H), 3.91 (s, 3H)

Chloro- 7- methoxyl group -1, the 6- naphthyridines (60) of 4-

By (332mg, compound 59 1.89mmol) is dissolved in 20ml acetonitrile, and (653 μ l, 3.95mmol) DIEA is added, stirring is lower to instill (345 μ l, 3.78mmol) phosphorus oxychloride, 70 DEG C are stirred to react 30min, are cooled to room temperature, after pour into ice water, pH to 8, EA extraction, the NH of saturation are adjusted with the NaOH of 2N₄The washing of Cl solution, saturation NaCl washing, anhydrous Na₂SO₄It is dry, it is concentrated under reduced pressure, column chromatographs to obtain target compound, yield 92%；¹H NMR (300MHz, CD₃OD) δ 9.33 (s, 1H), 8.85 (d, J=4.8Hz, 1H), 7.55 (d, J=4.8Hz, 1H), 7.23 (s, 1H), 4.10 (s, 3H)

N- (4- ((7- methoxyl group -1,6- benzodiazine -4- alkyl) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (3S)

The same 2S of synthetic route, initial feed are compound 60.¹H NMR (DMSO, 300MHz): δ 10.43 (s, 1H), 10.02 (s, 1H), 9.48 (s, 1H), 8.79 (d, J=5.2Hz, 1H), 7.94 (d, J=13.3Hz, 1H), 7.66 (dd, J=9.2,5.1Hz, 2H), 7.58-7.46 (m, 2H), 7.26 (s, 1H), 7.17 (t, J=8.9Hz, 2H), 6.49 (d, J=5.1Hz, 1H), 4.04 (s, 3H), 1.55-1.36 (m, 4H)

The synthesis of 8 4- of embodiment ((the bromo- 7- of 8- (2- morpholine ethyoxyl) -1,6- benzodiazine -4- alkyl) oxygroup) -3- fluoroaniline (4S)

Chloro- 7- methoxyl group -1, the 6- naphthyridines (61) of the bromo- 4- of 8-

The compound 58 of (482mg, 1.89mmol) is dissolved in 10ml DMF, lower instillation (345 μ l, 3.78mmol) phosphorus oxychloride is stirred, reaction 30min, TLC tracking is stirred at room temperature, pours into ice water after the reaction was completed, pH to 8, EA extraction, the NH of saturation are adjusted with the NaOH of 2N₄The washing of Cl solution, saturation NaCl washing, anhydrous Na₂SO₄It is dry, it is concentrated under reduced pressure, column chromatographs to obtain target compound, yield 83%；¹H NMR (300MHz, CDCl₃) (s, the 3H) of δ 9.25 (s, 1H), 8.94 (d, J=4.7Hz, 1H), 7.39 (d, J=4.7Hz, 1H), 4.18

Chloro- 7- hydroxyl -1, the 6- naphthyridines (62) of the bromo- 4- of 8-

Take 3ml trifluoromethanesulfonic acid in a round bottom flask, (516mg is added portionwise under ice bath, compound 61 1.89mmol), 180 DEG C of oil baths are moved into after stirring and dissolving and are stirred to react 10min, and TLC tracking is cooled to room temperature after the reaction was completed, be added a small amount of EA rush it is dilute, a large amount of DCM is added, standing obtains a large amount of solids, filters.Filter cake is dissolved with MeCN, is adjusted pH to 8 with the NaOH of 2N, is obtained a large amount of yellow solids.It filters, quickly column obtains target compound, yellow solid, yield 84% after filtration cakes torrefaction；¹H NMR (300MHz, DMSO) δ 8.86 (s, 1H), 8.55 (d, J=4.6Hz, 1H), 7.00 (d, J=4.8Hz, 1H)

Chloro- 1, the 6- naphthyridines (63) of 7- (4- morpholine ethyoxyl) the bromo- 4- of -8-

The compound 62 of (1.5g, 5.79mmol) is dissolved in 40ml THF, (1.14g is added with stirring, 8.69mmol) 4- hydroxyethyl morpholine, (1.58g, 8.69mmol) anhydrous magnesium sulfate, 10min is stirred at room temperature, it is rear that (2.28g, 8.69mmol) triphenylphosphine is added, (1.7ml is slowly added dropwise, 6h, TLC tracking is stirred at room temperature in 8.69mmol) DEAD, EA is extracted after the reaction was completed, is saturated NaHCO₃It washing twice and takes organic phase, dilute HCl of the organic phase with pH equal to 3 is washed twice, and takes inorganic phase, and pH, which is adjusted, with the NaOH of 2N extracts equal to 8, EA, saturation NaCl washing, anhydrous Na₂SO₄It is dry, it is concentrated under reduced pressure, column chromatographs to obtain target compound, yield 73%；¹H NMR (300MHz, CDCl₃) δ 9.23 (s, 1H), 8.95 (d, J=4.7Hz, 1H), 7.62 (d, J=4.6Hz, 1H), 4.72 (t, J=5.7Hz, 2H), 3.77-3.62 (m, 4H), 2.89 (t, J=5.8Hz, 2H), 2.70-2.56 (m, 4H)

4- ((the bromo- 7- of 8- (2- morpholine ethyoxyl) -1,6- benzodiazine -4- alkyl) oxygroup) -3- fluoroaniline (4S)

The same 2S of synthetic route, initial feed are 63 and to hydroxyl -3- fluoroanilines.¹H NMR (DMSO, 300MHz): δ 9.40 (s, 1H), 8.87 (d, J=5.3Hz, 1H), 7.15 (t, J=9.0Hz, 1H), 6.63-6.53 (m, 2H), 6.50 (d, J=8.6Hz, 1H), 5.58 (s, 2H), 4.67 (t, J=5.7Hz, 2H), 3.63-3.52 (m, 4H), 2.89-2.75 (m, 2H), 2.63-2.53 (m, 4H)

The fluoro- N of 9 2- of embodiment¹(7- (2- morpholine ethyoxyl) -1,6- benzodiazine -4- alkyl) phenyl-Isosorbide-5-Nitrae-diamines (5S) synthesis

The compound 4S of (0.93g, 2mmol) is dissolved in 40ml methanol, (0.18g is added, ammonium formate 4mmol), the 10%Pd/C of 20mg is added afterwards, 30min, TLC tracking are reacted at 60 DEG C, after the reaction was completed, cold filtration, filtrate concentration, after extracted with EA, saturation and NaCl washing, anhydrous Na₂SO₄It is dry, column is concentrated under reduced pressure and chromatographs to obtain product.¹H NMR (400MHz, DMSO) δ 11.15 (s, 1H), 9.38 (s, 1H), 8.84 (d, J=5.1Hz, 1H), 7.83 (d, J=12.3Hz, 1H), 7.38-7.30 (m, 1H), 7.29-7.17 (m, 1H), 6.44 (d, J=5.3Hz, 1H), 4.74 (t, J=5.7Hz, 2H), 3.74 (d, J=5.2Hz, 4H), 2.91 (t, J=9.8Hz, 2H), 2.76-2.62 (m, 4H).

10 N- of embodiment (4- ((the bromo- 7- of 8- (2- morpholine ethyoxyl) -1,6- benzodiazine -4- alkyl) oxygroup) -3- fluorophenyl) and-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (6S) synthesis

The same 2S of synthetic route, initial feed are compound 63 and compound 26.¹H NMR (DMSO, 300MHz): 10.43 (s of δ, 1H), 10.02 (s, 1H), 9.45 (s, 1H), 8.77 (d, J=5.4Hz, 1H), 7.93 (d, J=13.0Hz, 1H), 7.68-7.59 (m, 2H), 7.57-7.47 (m, 2H), 7.22 (s, 1H), 7.18-7.12 (m, 1H), 6.47 (d, J=5.1Hz, 1H), 4.49 (t, J=5.8Hz, 2H), 2.75 (t, J=5.4Hz, 2H), 2.57-2.51 (m, 4H), 2.41-2.26 (m, 4H), 2.15 (s, 3H), 1.5 (5-1.43 m, 4H)

11 N- of embodiment (the fluoro- 4- of 3- ((7- (2- morpholine ethyoxyl) -1,6- benzodiazine -4- alkyl) oxygroup) phenyl) and-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (7S) synthesis

Synthetic route same 5S, initial feed 6S.¹H NMR (DMSO, 300MHz): 10.43 (s of δ, 1H), 10.01 (s, 1H), 9.45 (s, 1H), 8.78 (d, J=5.2Hz, 1H), 7.93 (d, J=13.9Hz, 1H), 7.65 (dd, J=8.7, 5.1Hz, 2H), 7.60-7.45 (m, 2H), 7.24 (s, 1H), 7.17 (t, J=8.8Hz, 2H), 6.48 (d, J=5.2Hz, 1H), 4.52 (t, J=5.6Hz, 2H), 3.65-3.53 (m, 4H), 2.77 (t, J=5.6Hz, 2H), 2.56-2.50 (m, 4H), 1.5 4-1.40 (m, 4H)

12 N- of embodiment (the fluoro- 4- of 3- ((7- (2- morpholine propoxyl group) -1,6- benzodiazine -4- alkyl) oxygroup) phenyl) and-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (8S) synthesis

Chloro- 7- hydroxyl -1, the 6- naphthyridines (64) of 4-

Take 3ml trifluoromethanesulfonic acid in a round bottom flask, (367mg is added portionwise under ice bath, 1.89mmol) 60,150 DEG C of oil baths are moved into after stirring and dissolving and are stirred to react 2h, and TLC tracking is cooled to room temperature after the reaction was completed, after pour into ice, pH to 8, EA more times extractions, concentration are adjusted with the NaOH of 2N.Quick column obtains target compound, and yellow solid, since compound is unstable, yield is unstable, yield 41%；¹H NMR (300MHz, DMSO) δ 11.57 (s, 1H), 9.16 (s, 1H), 8.83 (d, J=4.7Hz, 1H), 7.52 (d, J=4.7Hz, 1H), 7.01 (s, 1H)

4- (3- ((chloro- 1, the 6- naphthyridines -7- alkyl of 4-) oxygroup) propyl) morpholine (65)

For synthetic route with compound 63, initial feed is N- (3- hydroxypropyl) morpholine.¹H NMR(CDCl₃, 300MHz): δ 9.31 (s, 1H), 8.80 (d, J=4.7Hz, 1H), 7.32 (d, J=4.6Hz, 1H), 7.25 (s, 1H), 4.45 (t, J=6.3Hz, 2H), 3.73-3.65 (m, 4H), 2.60-2.53 (m, 2H), 2.52-2.43 (m, 4H), 2.05 (t, J=7.0Hz, 2H)

N- (the fluoro- 4- of 3- ((7- (2- morpholine propoxyl group) -1,6- benzodiazine -4- alkyl) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (8S)

For synthetic route with compound 2S, initial feed is compound 65 and compound 26.¹H NMR (DMSO, 300MHz): δ 10.43 (s, 1H), 10.01 (s, 1H), 9.45 (s, 1H), 8.77 (d, J=5.2Hz, 1H), 7.94 (d, J=12.3Hz, 1H), 7.73-7.61 (m, 2H), 7.60-7.44 (m, 2H), 7.27-7.11 (m, 3H), 6.48 (d, J=5.1Hz, 1H), 4.43 (t, J=6.3Hz, 2H), 3.72-3.54 (m, 4H), 2.49-2.21 (m, 5H), 2.04-1.90 (m, 2H), 1.55-1.36 (m, 4H)

13 N- of embodiment (the fluoro- 4- of 3- ((7- ((1- methyl piperidine -4- alkyl) methoxyl group) -1,6- benzodiazine -4- alkyl) oxygroup) phenyl) and-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (9S) synthesis

The chloro- 7- of 4- ((1- methyl piperidine -4- alkyl) methoxyl group) -1,6- naphthyridines (66)

With compound 63, initial feed is 4- piperidine carbinols, yield 63% for the synthesis of compound 66.¹H NMR (300MHz, CDCl₃) δ 9.27 (s, 1H), 8.77 (d, J=4.7Hz, 1H), 7.28 (d, J=4.7Hz, 1H), 7.20 (s, 1H), 4.21 (d, J=6.2Hz, 2H), 2.87 (d, J=11.4Hz, 2H), 2.33-2.21 (s, 3H), 1.95-1.82 (m, 4H), 1.54-1.34 (m, 2H), 1.33-1.16 (m, 1H)

N- (the fluoro- 4- of 3- ((7- ((1- methyl piperidine -4- alkyl) methoxyl group) -1,6- benzodiazine -4- alkyl) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (9S)

For synthetic route with compound 2S, initial feed is compound 66 and compound 26.¹H NMR (DMSO, 300MHz): 10.48 (s of δ, 1H), 10.05 (s, 1H), 9.46 (s, 1H), 8.78 (d, J=5.3Hz, 1H), 7.95 (d, J=13.1Hz, 1H), 7.72-7.61 (m, 2H), 7.61-7.43 (m, 2H), 7.25 (s, 1H), 7.16 (t, J=7.9Hz, 2H), 6.49 (d, J=5.2Hz, 1H), 4.32 (d, J=6.1Hz, 2H), 3.01-2.79 (m, 2H), 2.69 (s, 3H), 2.19-1.87 (m, 3H), 1.77-1.57 (m, 2H), 1.56-1.32 (m, 4H)

14 N- of embodiment (4- ((the bromo- 7- of 8- (2- (4- methyl piperazine -1- alkyl) ethyoxyl) -1,6- benzodiazine -4- alkyl) oxygroup) -3-- fluorophenyl) and-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (10S) synthesis

The chloro- 7- of the bromo- 4- of 8- (2- (4- methyl piperazine -1- alkyl) ethyoxyl) -1,6- naphthyridines (67)

For synthetic route with 63, initial feed is compound 62 and 1- (2- ethoxy) -4- methyl piperazine.¹H NMR(CDCl₃, 300MHz): δ 9.20 (s, 1H), 8.92 (d, J=4.7Hz, 1H), 7.37 (d, J=4.7Hz, 1H), 4.69 (t, J=5.9Hz, 2H), 2.89 (t, J=5.9Hz, 2H), 2.79-2.61 (m, 4H), 2.54-2.34 (m, 4H), 2.26 (s, 3H)

N- (4- ((the bromo- 7- of 8- (2- (4- methyl piperazine -1- alkyl) ethyoxyl) -1,6- benzodiazine -4- alkyl) oxygroup) -3-- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (10S)

For synthetic route with compound 2S, initial feed is compound 67 and compound 26.¹H NMR (DMSO, 300MHz): δ 10.47 (s, 1H), 10.02 (s, 1H), 9.43 (s, 1H), 8.89 (d, J=5.3Hz, 1H), 7.95 (d, J=12.4Hz, 1H), 7.77-7.44 (m, 3H), 7.17 (t, J=8.2Hz, 2H), 6.62 (d, J=5.4Hz, 1H), 4.66 (t, J=5.1Hz, 2H), 3.41-3.24 (m, 4H), 2.85 (t, J=5.4Hz, 2H), 2.78-2.57 (m, 4H), 2.39 (s, 3H), 1.56-1.32 (m, 4H)

15 N- of embodiment (the fluoro- 4- of 3- ((7- (2- (4- methyl piperazine -1- alkyl) ethyoxyl) -1,6- benzodiazine -4- alkyl) oxygroup) phenyl) and-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (11S) synthesis

For synthetic route with compound 5S, initial feed is compound 10S.¹H NMR (DMSO, 300MHz): δ 10.43 (s, 1H), 10.02 (s, 1H), 9.45 (s, 1H), 8.77 (d, J=5.4Hz, 1H), 7.93 (d, J=13.0Hz, 1H), 7.68-7.59 (m, 2H), 7.57-7.47 (m, 2H), 7.22 (s, 1H), 7.18-7.12 (m, 1H), (6.47 d, J=5.1Hz, 1H) 4.49 (t, J=5.8Hz, 2H), 2.75 (t, J=5.4Hz, 2H), 2.57-2.51 (m, 4H), 2.41-2.26 (m, 4H), 2.15 (s, 3H), 1.55-1.43 (m, 4H)

16 N- of embodiment (4- fluorophenyl)-N- (4- ((7- (2- morpholine ethyoxyl) -1,6- benzodiazine -4- alkyl) oxygroup) phenyl) and cyclopropyl -1,1- diamides (12S) synthesis

4- (2- ((chloro- 1, the 6- naphthyridines -7- alkyl of 4-) oxygroup) ethyl) morpholine (68)

For synthetic route with compound 63, initial feed is compound 64 and 4- hydroxyethyl morpholine.¹H NMR (DMSO, 300MHz): δ 9.27 (s, 1H), 8.77 (d, J=4.7Hz, 1H), 7.29 (d, J=4.7Hz, 1H), 7.24 (s, 1H), 4.54 (t, J=5.8Hz, 2H), 3.72-3.66 (m, 4H), 2.83 (t, J=5.8Hz, 2H), 2.61-2.53 (m, 4H)

N- (4- fluorophenyl)-N- (4- ((7- (2- morpholine ethyoxyl) -1,6- benzodiazine -4- alkyl) oxygroup) phenyl) cyclopropyl -1,1- diamides (12S)

For synthetic route with compound 2S, initial feed is compound 68 and compound 31.¹H NMR (DMSO, 300MHz): 10.24 (s of δ, 1H), 10.06 (s, 1H), 9.42 (s, 1H), 8.75 (d, J=5.2Hz, 1H), 7.80 (d, J=9.1Hz, 2H), 7.71-7.57 (m, 2H), 7.31 (d, J=9.0Hz, 2H), 7.23-7.10 (m, 3H), 6.43 (d, J=5.2Hz, 1H), 4.52 (t, J=7.2Hz, 2H), 3.58 (d, J=4.9Hz, 4H), 2.77 (t, J=7.1Hz, 2H), 2.52 (m, 4H), 1.63-1.38 (m, 2H)

17 N- of embodiment (4- fluorophenyl)-N- (4- ((7- (2- morpholine ethyoxyl) -1,6- benzodiazine -4- alkyl) amino) phenyl) and cyclopropyl -1,1- diamides (13S) synthesis

The compound 68 of 1eq is dissolved in dry DMF solution, it is rear to be added the 68 of 1.2eq, it is warming up to 130 DEG C and is stirred to react, TLC tracking, addition EA is rushed dilute after the reaction was completed, with the NH of saturation₄The washing of Cl solution, saturation NaCl washing, anhydrous Na₂SO₄It is dry, it is concentrated under reduced pressure, column chromatographs to obtain target compound；Yield 72%.¹H NMR (DMSO, 300MHz): δ 10.16 (s, 1H), 10.07 (s, 1H), 9.47 (s, 1H), 8.42 (s, 1H), 7.84-7.59 (m, 5H), 7.33 (d, J=8.6Hz, 2H), 7.17 (t, J=8.8Hz, 2H), 6.98 (s, 1H), 6.61 (d, J=5.6Hz, 1H), 4.47 (t, J= 5.9Hz, 2H), 3.66-3.55 (m, 4H), 2.76 (t, J=5.7Hz, 2H), 2.51-2.48 (m, 4H), 1.55-1.39 (m, 4H)

18 N- of embodiment (the fluoro- 4- of 3- ((7- (2- morpholine ethyoxyl) -1,6- benzodiazine -4- alkyl) oxygroup) phenyl) and-N- (4- fluorophenyl)-N- methylcyclopropyl groups -1,1- diamides (14S) synthesis

For synthetic route with compound 2S, initial feed is compound 68 and compound 27.¹H NMR (DMSO, 300MHz): 10.00 (s of δ, 1H), 9.45 (s, 1H), 8.79 (d, J=5.0Hz, 1H), 7.60-7.39 (m, 3H), 7.37-7.27 (m, 2H), 7.24 (s, 1H), 7.21-7.05 (m, 2H), 6.46 (d, J=5.1Hz, 1H), 4.52 (t, J=6.3Hz, 2H), 3.66-3.51 (m, 4H), 3.25 (s, 3H), 2.77 (t, J=6.0Hz, 2H), 2.56-2.49 (m, 4H), 1.51-1.38 (m, 2H), 1.30-1.20 (m, 2H)

22 N- of embodiment (the fluoro- 4- of 3- ((7- (2- morpholine ethyoxyl) -1,6- benzodiazine -4- alkyl) oxygroup) phenyl) and -1- (4- fluorophenyl) -2- oxo -1,2- dihydropyridine -3- carbamide (15S) synthesis

For synthetic route with compound 2S, initial feed is compound 68 and compound 36.¹H NMR (DMSO, 300MHz): δ 12.18 (s, 1H), 9.52 (s, 1H), 8.83 (d, J=5.3Hz, 1H), 8.61 (d, J=7.2Hz, 1H), 8.22-8.06 (m, 2H), 7.71-7.47 (m, 4H), 7.53-7.23 (m, 3H), 6.76 (t, J=7.5Hz, 1H), 6.61 (d, J=5.1Hz, 1H), 4.90-4.75 (m, 2H), 4.02-3.76 (m, 4H), 3.69-3.60 (m, 2H), 2.53-2.43 (m, 4H)

23 1- of embodiment (the fluoro- 4- of 3- ((7- (2- morpholine ethyoxyl) -1,6- benzodiazine -4- alkyl) oxygroup) phenyl) and-N- (4- fluorophenyl) -2- oxo -1,2- dihydropyridine -3- carbamide (16S) synthesis

For synthetic route with compound 2S, initial feed is compound 68 and compound 42.¹H NMR (DMSO, 300MHz): δ 11.65 (s, 1H), 9.46 (s, 1H), 8.74 (s, 2H), 7.74-7.60 (m, 3H), 7.56-7.40 (m, 2H), 7.38-7.30 (m, 1H), 7.28 (s, 1H), 7.02 (t, J=8.7Hz, 2H), 6.65 (t, J=7.1Hz, 1H), 6.48 (d, J=5.3Hz, 1H), 4.58 (t, J=5.3Hz, 2H), 3.82-3.66 (m, 4H), 2.88 (t, J=5.6Hz, 2H), 2.71-2.54 (m, 4H)

The synthesis of 24 1- of embodiment (the fluoro- 4- of 3- ((7- (2- morpholine ethyoxyl) -1,6- benzodiazine -4- alkyl) oxygroup) phenyl) -2- oxo -1,2- dihydropyridine -3- methyl formate (17S)

The synthesis of 1- (the fluoro- 4- hydroxy phenyl of 3-) -2- oxo -1,2- dihydropyridine -3- methyl formate (69)

3% trifluoromethanesulfonic acid in the TFA of (400mg, 1.13mmol) 25 solution 3ml, will be added, reaction is stirred at room temperature, TLC tracking, addition EA is rushed dilute after the reaction was completed, with the NH of saturation₄The washing of Cl solution, saturation NaCl washing, anhydrous Na₂SO₄It is dry, it is concentrated under reduced pressure, column chromatographs to obtain target compound.¹H NMR (DMSO, 300MHz): δ 10.31 (s, 1H), 8.11 (d, J=7.1Hz, 1H), 7.93 (d, J=4.6Hz, 1H), 7.34 (d, J=11.5Hz, 1H), 7.05 (s, 2H), 6.39 (t, J=6.3Hz, 1H), 3.76 (s, 3H)

The synthesis of 1- (the fluoro- 4- of 3- ((7- (2- morpholine ethyoxyl) -1,6- benzodiazine -4- alkyl) oxygroup) phenyl) -2- oxo -1,2- dihydropyridine -3- methyl formate (17S)

For synthetic route with compound 2S, initial feed is compound 68 and compound 69.¹H NMR(CDCl₃, 300MHz): δ 9.45 (s, 1H), 8.72 (d, J=5.2Hz, 1H), 8.27 (d, J=4.9Hz, 1H), 7.61 (d, J=4.7Hz, 2H), 7.49-7.37 (m, 2H), 7.29 (d, J=9.2Hz, 1H), 6.47-6.32 (m, 2H), 4.57 (t, J=5.8Hz, 2H), 3.91 (s, 3H), 3.79-3.65 (m, 4H), 2.88 (t, J=5.7Hz, 2H), 2.71-2.56 (m, 4H)

The synthesis of 25 N- of embodiment (4- ((the bromo- 7- of 8- (2- morpholine ethyoxyl) -1,6- benzodiazine -4- alkyl) oxygroup) -3-- fluorophenyl) -2- phenyl acetamide (18S)

(100mg, 0.22mmol) 4S is dissolved in 10ml THF, the DIEA of 3eq is added, is cooled to 0 DEG C.1.5eq phenyllacetyl chloride is slowly added into, continues that temperature is kept to be stirred to react 1h.After fully reacting, EA is added and rushes dilute, use The NH of saturation₄The washing of Cl solution, saturation NaCl washing, anhydrous Na₂SO₄It is dry, it is concentrated under reduced pressure, column chromatographs to obtain target compound.Yield 86%.¹H NMR(CDCl₃, 300MHz): δ 10.58 (s, 1H), 9.43 (s, 1H), 8.87 (d, J=5.3Hz, 1H), 7.92 (d, J=13.3Hz, 1H), 7.64-7.20 (m, 6H), 6.64 (d, J=5.2Hz, 1H), 4.67 (t, J=5.7Hz, 2H), 3.70 (s, 2H), 3.63-3.49 (m, 4H), 2.82 (t, J=6.0Hz, 2H), 2.60-2.50 (m, 4H)

26 N- of embodiment (4- ((the bromo- 7- of 8- (2- morpholine ethyoxyl) -1,6- benzodiazine -4- alkyl) oxygroup) -3- fluorophenyl) and -4- oxo -5- phenyl-Isosorbide-5-Nitrae-dihydropyridine -3- carbamide (19S) synthesis

By (100mg, 0.22mmol) compound 4S, (71mg, 0.33mmol) compound 47 is dissolved in 10ml DCM, and (130mg, 0.66mmol) HOBt, (89mg are added at room temperature, 0.66mmol) EDC, it is stirred at room temperature, TLC tracking reaction boils off most DCM after the reaction was completed, EA extraction is added, is saturated NaHCO₃It washes, the washing of pH=3, saturated brine washing adds anhydrous Na₂SO₄It is dry, it is concentrated to get crude product, column chromatographs to obtain target compound.Yield 63%.¹H NMR (DMSO, 300MHz): δ 13.60 (s, 1H), 9.44 (s, 1H), 8.89 (s, 1H), 8.65 (s, 1H), 8.26-8.04 (m, 2H), 7.74-7.63 (m, 2H), 7.63-7.30 (m, 5H), (6.69 d, J=5.4Hz, 1H), (4.68 t, J=5.7Hz, 2H), 3.64-3.53 (m, 4H), 2.81 (t, J=5.8Hz, 2H), 2.60-2.52 (m, 4H)

27 N- of embodiment (the fluoro- 4- of 3- ((7- (2- morpholine ethyoxyl) -1,6- benzodiazine -4- alkyl) oxygroup) phenyl) and -4- oxo -5- phenyl-Isosorbide-5-Nitrae-dihydropyridine -3- carbamide (20S) synthesis

For synthetic route with compound 5S, initial feed is compound 19S.¹H NMR (DMSO, 300MHz): δ 13.31 (s, 1H), 9.47 (s, 1H), 8.78 (d, J=5.2Hz, 1H), 8.65 (s, 1H), 8.17-8.04 (m, 2H), 7.67 (d, J=6.8Hz, 2H), 7.61-7.53 (m, 2H), 7.50-7.32 (m, 4H), 7.25 (s, 1H), 6.56 (d, J=5.2Hz, 1H), 4.54 (t, J=5.7Hz, 2H), 3.65-3.54 (m, 4H), 2.81 (t, J=6.8Hz, 2H), 2.58-2.52 (m, 4H)

28 N- of embodiment (4- ((the bromo- 7- of 8- (2- morpholine ethyoxyl) -1,6- benzodiazine -4- alkyl) oxygroup) -3- fluorophenyl) and -5- (4- fluorophenyl) -4- oxo-Isosorbide-5-Nitrae-dihydropyridine -3- carbamide (21S) synthesis

For synthetic route with compound 19S, initial feed is compound 4S and compound 48.¹H NMR (DMSO, 300MHz): δ 13.39 (s, 1H), 9.44 (s, 1H), 8.89 (d, J=5.3Hz, 1H), 8.65 (s, 1H), 8.18-8.03 (m, 2H), 7.81-7.65 (m, 2H), 7.55 (s, 2H), 7.34-7.20 (m, 2H), 6.68 (d, J=4.3Hz, 1H), 4.68 (t, J=5.6Hz, 2H), 3.61-3.54 (m, 4H), 2.81 (t, J=5.7Hz, 2H), 2.61-2.53 (m, 4H)

29 N- of embodiment (the fluoro- 4- of 3- ((7- (2- morpholine ethyoxyl) -1,6- benzodiazine -4- alkyl) oxygroup) phenyl) and -5- (4- fluorophenyl) -4- oxo-Isosorbide-5-Nitrae-dihydropyridine -3- carbamide (22S) synthesis

For synthetic route with compound 5S, initial feed is compound 21S.¹H NMR (DMSO, 300MHz): δ 13.26 (s, 1H), 9.46 (s, 1H), 8.78 (d, J=5.3Hz, 1H), 8.64 (s, 1H), 8.16-8.07 (m, 2H), 7.76-7.67 (m, 3H), 7.55-7.48 (m, 2H), 7.30-7.24 (m, 3H), 6.55 (d, J=5.4Hz, 1H), 4.54 (t, J=5.6Hz, 2H), 3.63-3.57 (m, 4H), 2.82 (t, J=7.3Hz, 2H), 2.61-2.52 (m, 4H)

30 N- (3 of embodiment, 4- difluorophenyl)-N- (the fluoro- 4- of 3- ((7- (2- morpholine ethyoxyl) -1,6- benzodiazine -4- alkyl) oxygroup) phenyl) and cyclopropyl -1,1- diamides (23S) synthesis

N- (4- ((the bromo- 7- of 8- (2- morpholine ethyoxyl) -1,6- benzodiazine -4- alkyl) oxygroup) -3- fluorophenyl)-N- (3,4- difluorophenyl) cyclopropyl -1,1- diamides (70)

For synthetic route with compound 2S, initial feed is compound 63 and compound 28.¹H NMR (DMSO, 300MHz): δ 10.40 (s, 1H), 10.21 (s, 1H), 9.43 (s, 1H), 8.89 (d, J=5.4Hz, 1H), 7.94 (d, J=13.6Hz, 1H), 7.89-7.75 (m, 1H), 7.64-7.48 (m, 2H), 7.46-7.32 (m, 2H), 6.62 (d, J=5.3Hz, 1H) 4.68 (t, J=5.7Hz, 2H), 3.67-3.52 (m, 4H), 2.83 (t, J=6.0Hz, 2H), 2.68-2.54 (m, 4H), 1.57-1.41 (m, 4H)

N- (3,4- difluorophenyl)-N- (the fluoro- 4- of 3- ((7- (2- morpholine ethyoxyl) -1,6- benzodiazine -4- alkyl) oxygroup) phenyl) cyclopropyl -1,1- diamides (23S)

For synthetic route with compound 5S, initial feed is compound 70.¹H NMR(CD₃OD, 300MHz): δ 9.48 (d, J=0.6Hz, 1H), 8.71 (d, J=5.4Hz, 1H), 7.86 (d, J=12.7Hz, 1H), 7.71 (dd, J=11.7,6.3Hz, 1H), 7.46-7.36 (m, 2H), 7.28-7.15 (m, 3H), 6.52 (d, J=5.4Hz, 1H), 4.70-4.64 (m, 2H), 3.80-3.71 (m, 4H), 3.08-3.01 (m, 2H), 2.85-2.75 (m, 4H), 1.64 (m, 4H)

31 N- of embodiment (the fluoro- 3- methoxyl group of 4-)-N- (the fluoro- 4- of 3- ((7- (2- morpholine ethyoxyl) -1,6- benzodiazine -4- alkyl) oxygroup) phenyl) and cyclopropyl -1,1- diamides (24S) synthesis

N- (4- ((the bromo- 7- of 8- (2- morpholine ethyoxyl) -1,6- benzodiazine -4- alkyl) oxygroup) -3- fluorophenyl)-N- (3- methoxyl group -4- fluorophenyl) cyclopropyl -1,1- diamides (71)

For synthetic route with compound 2S, initial feed is compound 63 and compound 29.¹H NMR (DMSO, 300MHz): δ 10.40 (s, 1H), 10.00 (s, 1H), 9.43 (s, 1H), 8.88 (d, J=7.4Hz, 1H), 7.94 (d, J=12.9Hz, 1H), 7.64-7.50 (m, 3H), 7.25-7.14 (m, 2H), 6.60 (d, J=8.2Hz, 1H), 4.66 (t, J=6.1Hz, 2H), 3.81 (s, 3H), 3.64-3.55 (m, 4H), 2.80 (t, J=8.4Hz, 2H), 2.65-2.55 (m, 4H), 1.54-1.44 (m, 4H)

N- (the fluoro- 3- methoxyl group of 4-)-N- (the fluoro- 4- of 3- ((7- (2- morpholine ethyoxyl) -1,6- benzodiazine -4- alkyl) oxygroup) phenyl) cyclopropyl -1,1- diamides (24S)

For synthetic route with compound 5S, initial feed is compound 71.¹H NMR (DMSO, 300MHz): 9.97 (s of δ, 1H), 9.44 (s, 1H), 9.32 (s, 1H), 8.68 (d, J=5.1Hz, 1H), 8.30 (s, 1H), 7.80 (t, J=12.8Hz, 1H), 7.45-7.29 (m, 2H), 7.23-7.19 (m, 1H), 7.06-6.83 (m, 2H), 6.32 (t, J=4.9Hz, 1H), 4.56 (t, J=5.7Hz, 2H), 3.89 (s, 3H), 3.79-3.69 (m, 4H), 2.88 (t, J=5.8Hz, 2H), 2.68-2.57 (m, 4H), 1.83- 1.75 (m, 2H), 1.68-1.57 (m, 2H)

32 N- of embodiment (the fluoro- 4- of 3- ((7- (2- (pyridine -4- alkyl) ethyoxyl) -1,6- benzodiazine -4- alkyl) oxygroup) phenyl) and-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (25S) synthesis

The chloro- 7- of the bromo- 4- of 8- (2- (pyridine -4- alkyl) ethyoxyl) -1,6- benzodiazine (72)

For synthetic route with compound 63, initial feed is compound 62 and 1- (2- ethoxy) pyridine.¹H NMR(CDCl₃, 300MHz): δ 9.21 (s, 1H), 8.94 (d, J=4.7Hz, 1H), 8.52 (d, J=5.9Hz, 2H), 7.40 (d, J=4.7Hz, 1H), 7.30 (d, J=5.9Hz, 2H), 4.77 (t, J=6.5Hz, 2H), 3.18 (t, J=6.5Hz, 2H)

N- (4- ((the bromo- 7- of 8- (2- (pyridine -4- alkyl) ethyoxyl) -1,6- benzodiazine -4- alkyl) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (73)

For synthetic route with compound 2S, initial feed is compound 72 and compound 26.¹H NMR (DMSO, 300MHz): 10.44 (s of δ, 1H), 10.01 (s, 1H), 9.44 (s, 1H), 8.89 (d, J=5.3Hz, 1H), 8.51 (d, J=7.6Hz, 2H), 7.94 (d, J=13.9Hz, 1H), 7.69-7.62 (m, 2H), 7.58-7.48 (m, 2H), 7.49-7.37 (m, 2H), 7.17 (t, J=8.9Hz, 2H), 6.62 (d, J=6.2Hz, 1H), 4.80 (t, J=7.2Hz, 2H), 3.16 (t, J=7.2Hz, 2H), 1.54-1.43 (m, 4H)

N- (the fluoro- 4- of 3- ((7- (2- (pyridine -4- alkyl) ethyoxyl) -1,6- benzodiazine -4- alkyl) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (25S)

For synthetic route with compound 5S, initial feed is compound 73.¹H NMR(CDCl₃, 300MHz): 10.19 (s of δ, 1H), 9.44 (s, 1H), 8.68 (d, J=5.2Hz, 1H), 8.52 (d, J=6.0Hz, 2H), 8.10 (s, 1H), 7.78 (dd, J=12.1, 2.3Hz, 1H), 7.48-7.38 (m, 2H), 7.29-7.25 (m, 3H), 7.21 (m, 2H), 7.10-6.99 (m, 2H), 6.33 (d, J=5.4Hz, 1H), 4.67 (t, J=6.7Hz, 2H), 3.17 (t, J=6.6Hz, 2H), 1.86-1.76 (m, 2H), 1.61-1.57 (m, 2H)

33 N- of embodiment (the fluoro- 4- of 3- ((7- ((1- morpholine propyl -2- alkyl) oxygroup) -1,6- benzodiazine -4- alkyl) oxygroup) phenyl) and-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (26S) synthesis

4- (2- ((chloro- 1, the 6- benzodiazine -7- alkyl of the bromo- 4- of 8-) oxo) propyl) morpholine (74)

For synthetic route with compound 63, initial feed is compound 62 and N- (2- hydroxypropyl) morpholine.¹H NMR(CDCl₃, 300MHz): δ 9.21 (s, 1H), 8.93 (d, J=4.7Hz, 1H), 7.38 (d, J=4.7Hz, 1H), 5.68-5.57 (m, 1H), 3.57 (t, J=4.6Hz, 4H), 2.65-2.50 (m, 4H), 1.81-1.66 (m, 2H), 1.43 (d, J=6.2Hz, 3H)

N- (4- ((the bromo- 7- of 8- ((1- morpholine propyl -2- alkyl) oxygroup) -1,6- benzodiazine -4- alkyl) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (75)

For synthetic route with compound 2S, initial feed is compound 74 and compound 26.¹H NMR(CDCl₃, 300MHz): 110.20 (s of δ, 1H), 9.35 (s, 1H), 8.81 (d, J=5.3Hz, 1H), 8.00 (s, 1H), 7.78 (d, J=12.4Hz, 1H), 7.48-7.38 (m, 2H), 7.28-7.25 (m), 7.06 (t, J=8.6Hz, 2H), 6.40 (d, J=5.4Hz, 1H), 5.72-5.59 (m, 1H), 3.60 (t, J=4.4Hz, 4H), 2.63-2.53 (m, 4H), 1.86-1.78 (m, 2H), 1.63-1.58 (m, 4H), 1.45 (d, J=6.3Hz, 3H)

N- (the fluoro- 4- of 3- ((7- ((1- morpholine propyl -2- alkyl) oxygroup) -1,6- benzodiazine -4- alkyl) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (26S)

For synthetic route with compound 5S, initial feed is compound 75.¹H NMR (DMSO, 300MHz): 10.43 (s of δ, 1H), 10.01 (s, 1H), 9.44 (s, 1H), 8.75 (d, J=5.2Hz, 1H), 7.93 (dd, J=13.1, 2.3Hz, 1H), 7.64 (dd, J=9.1, 5.0Hz, 2H), 7.59-7.45 (m, 2H), 7.22-7.10 (m, 3H), 6.46 (d, J=5.2Hz, 1H), 5.58-5.46 (m, 1H), 3.55-3.48 (m, 4H), 2.78-2.56 (m, 2H), 2.50-2.43 (m, 4H), 1.52-1.44 (m, 4H), 1. 34 (d, J=6.2Hz, 3H)

The synthesis of 34 N- of embodiment (the fluoro- 4- of 3- ((7- morpholine -1,6- benzodiazine -4- alkyl) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (27S)

7- morpholine -1,6- benzodiazine -4 (1H) -one (76)

The compound 52 of (340mg, 1.89mmol) is dissolved in morpholine, 1h is reacted at 190 DEG C, TLC tracking is cooled to room temperature after the reaction was completed, and ether precipitating, filtering is added, and ether washes to obtain crude product.¹H NMR (DMSO, 400MHz): δ 8.83 (s, 1H), 7.74 (d, J=7.6Hz, 1H), 6.45 (s, 1H), 5.87 (d, J=7.6Hz, 1H), 3.75-3.65 (m, 4H), 3.54-3.45 (m, 4H)

N- (the fluoro- 4- of 3- ((7- morpholine -1,6- benzodiazine -4- alkyl) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (27S)

For synthetic route with compound 2S, initial feed is compound 76.¹H NMR (DMSO, 400MHz): δ 10.54 (s, 1H), 10.02 (s, 1H), 9.55 (s, 1H), 8.84 (d, J=6.0Hz, 1H), 7.99 (d, J=12.8Hz, 1H), 7.72-7.62 (m, 2H), 7.62-7.51 (m, 2H), 7.17 (t, J=8.5Hz, 2H), 7.03 (s, 1H), (6.63 d, J=7.1Hz, 1H), 3.84-3.76 (m, 4H), 3.75-3.69 (m, 4H), 1.57-1.43 (m, 4H)

The synthesis of 35 N- of embodiment (the fluoro- 4- of 3- ((7- (4- morpholine piperidin-1-yl)-benzodiazine -4- alkyl) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (28S)

For synthetic route with compound 27S, initial feed is 4- (4- piperidyl) morpholine.¹H NMR(CDCl₃, 300MHz): 10.05 (s of δ, 1H), 9.39 (s, 1H), 8.55 (d, J=5.3Hz, 1H), 8.15 (s, 1H), 7.75 (d, J=12.5Hz, 1H), 7.43 (dd, J=9.3, 4.4Hz, 2H), 7.23-7.16 (m, 1H), 7.05 (t, J=8.8Hz, 2H), 6.96 (s, 1H), 6.17 (d, J=4.7Hz, 1H), 4.50 (d, J=12.3Hz, 2H), 3.84-3.63 (m, 4H), 3.04-2.85 (m, 2H), 2.67-2.54 (m, 4H), 2.52-2.41 (m, 1H), 2.04-1.92 (m, 2H), 1.87-1.75 (m, 2H), 1.69-1.54 (m, 4H)

The synthesis of embodiment 36 (S)-N- (the fluoro- 4- of 3- ((7- (2- (3- methylmorpholine) ethyoxyl)-benzodiazine -4- alkyl) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (29S)

For synthetic route with compound 26S, initial feed is compound 62 and (S) -2- (3- methyl morpholine) ethyl alcohol.¹H NMR(CDCl₃, 300MHz): δ 10.17 (s, 1H), 9.45 (s, 1H), 8.68 (d, J=5.2Hz, 1H), 8.10 (s, 1H), 7.77 (d, J=12.3Hz, 1H), 7.43 (dd, J=9.0,4.8Hz, 2H), 7.30-7.22 (m, 3H), (7.05 t, J=8.6Hz, 2H), (6.32 d, J=4.9Hz, 1H), (4.53 t, J=6.0Hz, 2H), (3.80 d, J=11.5Hz, 1H), 3.72-3.60 (m, 2H) 3.31-3.15 (m, 2H), 2.95-2.74 (m, 2H), 2.65-2.51 (m, 2H), 1.85-1.77 (m, 2H), 1.63-1.56 (m, 2H), 1.04 (d, J=6.3Hz, 3H)

The synthesis of embodiment 37 (R)-N- (the fluoro- 4- of 3- ((7- (2- (3- methylmorpholine) ethyoxyl)-benzodiazine -4- alkyl) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (30S)

For synthetic route with compound 26S, initial feed is compound 62 and (R) -2- (3- methyl morpholine) ethyl alcohol.¹H NMR(CDCl₃, 300MHz): 10.19 (s of δ, 1H), 9.45 (s, 1H), 8.68 (d, J=5.2Hz, 1H), 8.13 (s, 1H), 7.77 (d, J=12.5Hz, 1H), 7.55-7.35 (m, 2H), 7.27-7.19 (m, 2H), 7.05 (t, J=8.6Hz, 2H), 6.33 (d, J=5.2Hz, 1H), 4.55 (t, J=4.5Hz, 2H), 3.86-3.74 (m, 1H), 3.75-3.60 (m, 2H), 3.37-3.14 (m, 2H), 3.01-2.76 (m, 2H), 2.70-2.51 (m, 2H), 1.87 - 1.74 (m, 2H), 1.68-1.53 (m, 2H), 1.05 (d, J=6.1Hz, 3H)

The synthesis of 38 N- of embodiment (4- ((7- (2- (1H- imidazoles -1- base) ethyoxyl)-benzodiazine -4- alkyl) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (31S)

For synthetic route with compound 26S, initial feed is compound 62 and 2- (1H- imidazoles -1- alkyl) ethyl alcohol.¹H NMR(CDCl₃, 300MHz): δ 10.40 (s, 1H), 9.41 (s, 1H), 8.68 (d, J=5.3Hz, 1H), 8.55 (s, 1H), 7.78 (d, J=12.1Hz, 1H), 7.65 (s, 1H), 7.43 (dd, J=9.0,4.7Hz, 2H), (7.33-7.26 m, 1H), 7.24-7.15 (m, 2H), 7.11-6.97 (m, 4H), 6.34 (d, J=5.2Hz, 1H), 4.72 (t, J=5.3Hz, 2H), 4.41 (t, J=5.2Hz, 2H), 1.86-1.75 (m, 2H), 1.67-1.55 (m, 2H)

The synthesis of 39 N- of embodiment (4- ((7- (4- benzyl diethylenediamine base -1- base)-benzodiazine -4- alkyl) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (32S)

For synthetic route with compound 27S, initial feed is 4- Benzvlmorpholin.¹H NMR(CDCl₃, 300MHz): 10.03 (s of δ, 1H), 9.39 (s, 1H), 8.55 (d, J=5.3Hz, 1H), 8.18 (s, 1H), 7.74 (d, J=12.1Hz, 1H), 7.49-7.39 (m, 2H), 7.39-7.26 (m, 5H), 7.23-7.15 (m, 1H), 7.05 (t, J=8.5Hz, 2H), 6.92 (s, 1H), 6.18 (d, J=5.1Hz, 1H), 3.74-3.63 (m, 4H), 3.57 (s, 2H), 2.69-2.54 (m, 4H), 1.84-1.75 (m, 2H), 1.61-1.54 (m, 2H)

40 N- of embodiment (3- fluoro- 4- ((3- oxo -3,4- dihydropyridone [2,3-b] diazine -8- alkyl) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (33S) synthesis

The synthesis of N- (the fluoro- 4- of 3- ((2- oxo -1,2- dihydropyridone [2,3-b] diazine -8- alkyl) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (34S)

N- (4- ((2- amino -3- nitropyridine -4- alkyl) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (88)

2- amino -3- nitro -4- the chloropyridine of (1g, 5.8mmol) is dissolved in anhydrous DMF, the 26 of 1.1eq are added, it is rear that 1.1eq potassium tert-butoxide is added, use N₂Three times, 80 DEG C are stirred to react 1h, and TLC tracking, addition EA is rushed dilute after the reaction was completed, with the NH of saturation for displacement₄The washing of Cl solution, saturation NaCl washing, anhydrous Na₂SO₄It is dry, it is concentrated under reduced pressure, column chromatographs to obtain target compound, and 81%.¹H NMR (300MHz, DMSO) δ 10.64 (s, 1H), 9.94 (s, 1H), 8.05 (d, J=5.7Hz, 1H), 7.97 (t, J=8.6Hz, 1H), 7.62 (dd, J=9.0,5.0Hz, 2H), 7.32 (d, J=11.2Hz, 1H), 7.25 (s, 2H), 7.18 (t, J=8.9Hz, 2H), 7.06 (d, J=8.4Hz, 1H), 6.06 (d, J=5.6Hz, 1H), 1.58 (t, J=10.6Hz, 4H)

N- (4- ((2,3- diamino-pyridine -4- alkyl) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (89)

The compound 88 of 1eq is dissolved in 20ml THF/MeOH (V: V=1: 1) solution, the rear NiCl that 4eq is added₂·6H₂The NaBH of 2eq is added portionwise in O under stirring at 0 DEG C₄, continue to be stirred to react 10min, TLC tracking, addition EA is rushed dilute after the reaction was completed, with the NH of saturation₄The washing of Cl solution, saturation NaCl washing, anhydrous Na₂SO₄It is dry, it is concentrated under reduced pressure, column chromatographs to obtain target compound.¹H NMR (300MHz, CD₃OD) δ 8.02 (d, J=5.7Hz, 1H), 7.87 (dd, J=13.2,2.3Hz, 1H), 7.68-7.58 (m, 2H), 7.48 (d, J=9.0Hz, 1H), 7.36 (t, J=9.0Hz, 1H), 7.24 (s, 1H), 7.20-7.07 (m, 2H), 5.97 (d, J=5.7Hz, 1H), 1.52-1.40 (m, 4H)

The synthesis of N- (the fluoro- 4- of 3- ((3- oxo -3,4- dihydropyridone [2,3-b] diazine -8- alkyl) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (33S)

(100mg, 0.23mmol) compound 89 is dissolved in ethyl alcohol, under 60 DEG C of stirrings, the toluene solution of the aldehyde radical ethyl acetate of 2eq is added, continues to be stirred to react 3h, TLC tracking, addition EA is rushed dilute after the reaction was completed, with the NH of saturation₄The washing of Cl solution, saturation NaCl washing, anhydrous Na₂SO₄It is dry, it is concentrated under reduced pressure, column chromatographs to obtain target compound.Yield: 33S:31%, 34S:48%.33S:¹H NMR (DMSO, 300MHz): δ 12.96 (s, 1H), 10.40 (s, 1H), 10.01 (s, 1H), 8.37 (d, J=5.7Hz, 1H), 8.20 (s, 1H), (7.91 d, J=13.3Hz, 1H), 7.65 (dd, J=9.1,5.1Hz, 2H), 7.51 (d, J=8.0Hz, 1H), 7.39 (t, J=9.0Hz, 1H), 7.16 (t, J=8.9Hz, 2H), 6.56 (d, J=5.6Hz, 1H), 1.58-1.36 (m, 4H) .34S:¹H NMR (DMSO, 300MHz): δ 12.67 (s, 1H), 10.41 (s, 1H), 10.00 (s, 1H), 8.43 (s, 1H), 8.35 (d, J=5.4Hz, 1H), 7.89 (d, J=13.7Hz, 1H), 7.64 (dd, J=8.7,5.0Hz, 2H), 7.50 (d, J=9.2Hz, 1H), 7.40 (t, J=8.9Hz, 1H), 7.16 (t, J=8.9Hz, 2H), 6.81 (d, J=5.5Hz, 1H), 1.49-1.44 (m, 4H)

41 N- of embodiment (4- ((7- ((1- ethyl -3- fluorine resources -4- base) amino) -1,6- naphthyridines -4- base) oxygroup) -3- fluorophenyl) and -2- (4- fluorophenyl) -3- oxygen -2,3- dihydrogen dazin -4- carbamide (35S) synthesis

The same 27S of synthetic route, initial feed are N- ethyl -4- amino -3- fluorine resources.¹H NMR (DMSO, 300MHz): 9.06 (d of δ, J=15.0Hz, 1H), 8.93 (s, 1H), 8.82 (d, J=12.5Hz, 1H), 8.59 (d, J=12.3Hz, 1H), 7.55 (dd, J=16.0, 3.0Hz, 1H), 7.50-7.41 (m, 2H), 7.41-7.31 (m, 2H), 7.25 (d, J=14.8Hz, 1H), 7.16 (s, 1H), 7.12 (dd, J=14.9, 3.0Hz, 1H), 6.83 (dd, J=14.9, 10.0Hz, 1H), 5.23-4.91 (m, 1H), 4.06-3.80 ( M, 1H), 3.23-2.98 (m, 1H), 2.83-2.69 (m, 1H), 2.57-2.28 (m, 4H), 2.19-2.02 (m, 1H), 1.86-1.68 (m, 1H), 1.09 (t, J=12.6Hz, 3H)

42 N- of embodiment (the fluoro- 4- of 3- ((7- (2- morpholine -2- acetoxyl group) -1,6- benzodiazine -4- alkyl) oxygroup)-phenyl) and-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (36S) synthesis

For synthetic route with compound 26S, initial feed is compound 62 and 2- hydroxyl -1- morpholine acetamide.¹H NMR(CDCl₃, 300MHz): 10.07 (s of δ, 1H), 9.37 (s, 1H), 8.72 (s, 1H), 8.65 (d, J=5.3Hz, 1H), 7.62 (d, J=12.0Hz, 1H), 7.50-7.41 (m, 2H), 7.31 (s, 1H), 7.21-7.14 (m, 1H), 7.13-7.07 (m, 1H), 7.07-7.00 (m, 2H), 6.24 (d, J=5.9Hz, 1H), 5.18 (s, 2H), 3.79-3.68 (m, 4H), 3.68-3.56 (m, 4H), 1.80-1.72 (m, 2H), 1.62-1.57 (m, 2H)

43 N- of embodiment (the fluoro- 4- of 3- ((7- (2- (3- oxo morpholine) ethyoxyl) -1,6- benzodiazine -4- alkyl) oxygroup)-phenyl) and-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (37S) synthesis

For synthetic route with compound 26S, initial feed is compound 62 and 2- hydroxyethyl -2- morpholine ketone.¹H NMR(CDCl₃, 300MHz): 10.23 (s of δ, 1H), 9.43 (s, 1H), 8.68 (d, J=5.3Hz, 1H), 8.26 (s, 1H), 7.78 (d, J=12.0Hz, 1H), 7.43 (dd, J=8.9, 4.7Hz, 2H), 7.29 (d, J=8.8Hz, 1H), 7.24-7.17 (m, 2H), 7.05 (t, J=8.5Hz, 2H), 6.34 (d, J=5.2Hz, 1H), 4.63 (t, J=4.9Hz, 2H), 4.17 (s, 2H), 3.93-3.81 (m, 4H), 3.67-3.55 (m, 2H), 1.86-1.75 (m, 2H ), 1.65-1.54 (m, 2H)

44 N- of embodiment (the fluoro- 4- of 3- ((7- (1- methyl-1 hydrogen-pyrazoles -4- alkyl) -1,6- benzodiazine -4- alkyl) oxygroup)-phenyl) and-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (38S) synthesis

In the dioxane water that (50mg, 0.10mmol) compound 1S is dissolved in (v: v=3: 2), the rear potassium phosphate that 2eq is added, the 1- methyl -4- (4 of 2eq, 4,5,5- tetramethyls -1,3,2- dioxaborolan -2- bases) -1H- pyrazoles, N₂It protects and is stirred to react 3h at lower 130 DEG C, TLC tracking, addition EA is rushed dilute after the reaction was completed, with the NH of saturation₄The washing of Cl solution, saturation NaCl washing, anhydrous Na₂SO₄It is dry, it is concentrated under reduced pressure, column chromatographs to obtain target compound, yield 81%.¹H NMR(CDCl₃, 300MHz): δ 10.20 (s, 1H), 9.70 (s, 1H), 8.73 (d, J=5.4Hz, 1H), (8.23 s, 1H), 8.06 (d, J=8.3Hz, 2H), 7.96 (s, 1H), 7.78 (d, J=12.0Hz, 1H), 7.50-7.35 (m, 2H), 7.30-7.26 (m, 1H), 7.04 (t, J=8.6Hz, 2H), 6.46 (d, J=5.3Hz, 1H), 3.98 (s, 3H), 1.84-1.78 (m, 2H), 1.63-1.57 (m, 2H)

45 N- of embodiment (4- ((7- (1 hydrogen-pyrazoles -4- alkyl) -1,6- benzodiazine -4- alkyl) oxygroup) -3- fluorophenyl) and-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (39S) synthesis

For synthetic route with compound 38S, initial feed is compound 1S and 1- tert-butoxy formyl -4- (4,4,5,5- tetramethyls -1,3,2- dioxaborolan -2- base) -1H- pyrazoles.¹H NMR(CDCl₃, 300MHz): δ 9.61 (s, 1H), 8.64 (d, J=5.3Hz, 1H), 8.14 (s, 1H), 7.93 (s, 1H), 7.69 (d, J=12.0Hz, 1H), 7.41-7.31 (m, 2H), 7.31-7.20 (m, 2H), 7.20-7.06 (m, 1H), 6.91 (t, J=8.5Hz, 2H), 6.46 (d, J=5.3Hz, 1H), 1.69-1.49 (m, 4H)

46 N- of embodiment (the fluoro- 4- of 3- ((7- (1- (mesyl) -1 hydrogen-pyrazoles -4- alkyl) -1; 6- benzodiazine -4- alkyl) oxygroup)-phenyl) and-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (40S) synthesis

Compound 39S is dissolved in tetrahydrofuran, the lower DIEA that 2eq is added is stirred at room temperature, after be slowly added dropwise the methylsufonyl chloride of 1.1eq, continuation is stirred to react 30min at room temperature, TLC tracking, be added after the reaction was completed EA rush it is dilute, with the Na of saturation₂CO₃Solution washing, saturation NaCl washing, anhydrous Na 2SO4 is dry, is concentrated under reduced pressure, and column chromatographs to obtain target compound, yield 68%.¹H NMR(CDCl₃, 300MHz): δ 10.25 (s, 1H), 9.77 (s, 1H), 8.93-8.86 (m, 1H), 8.80 (d, J=6.0Hz, 1H), 8.69 (s, 1H), 8.43 (s, 1H), 8.07 (s, 1H), 7.99 (s, 1H), 7.80 (d, J=11.7Hz, 1H), 7.45-7.41 (m, 2H), 7.32-7.28 (m, 1H), 7.09-7.00 (m, 2H), 6.55 (d, J=5.5Hz, 1H), 3.41 (s, 3H), 1.85-1.80 (m, 2H), 1.59-1.57 (m, 2H)

47 N- of embodiment (the fluoro- 4- of 3- ((7- (1- (isopropyl) -1 hydrogen-pyrazoles -4- alkyl) -1,6- benzodiazine -4- alkyl) oxygroup)-phenyl) and-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (41S) synthesis

For synthetic route with compound 38S, initial feed is compound 1S and 1- isopropyl -4- (4,4,5,5- tetramethyls -1,3,2- dioxaborolan -2- base) -1H- pyrazoles.¹H NMR(CDCl₃, 300MHz): 10.22 (s of δ, 1H), 9.75 (d, J=0.8Hz, 1H), 8.78 (d, J=5.3Hz, 1H), 8.18 (s, 2H), 8.13 (s, 1H), 8.02 (d, J=0.8Hz, 1H), 7.83 (dd, J=12.1, 2.2Hz, 1H), 7.50-7.43 (m, 2H), 7.33-7.31 (m, 1H), 7.30-7.29 (m, 1H), 7.14-7.05 (m, 2H), 6.50 (dd, J=5.3, 1.2Hz, 1H), 4.61 (dt, J=13.4, 6.7Hz, 1H), 1.85 (dd, J=7.9, 4.8 Hz, 2H), 1.65-1.60 (m, 8H)

48 N- of embodiment (the fluoro- 4- of 3- ((7- (1- (- 4 alkyl of piperidines) -1 hydrogen-pyrazoles -4- alkyl) -1,6- benzodiazine -4- alkyl) oxygroup)-phenyl) and-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (42S) synthesis

With compound 38S, initial feed is compound 1S and 4- [4- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) -1H- pyrazol-1-yl] piperidines -1- t-butyl formate for the synthesis of compound 96.¹H NMR(CDCl₃, 300MHz): 10.21 (s of δ, 1H), 9.70 (s, 1H), 8.74 (d, J=5.3Hz, 1H), 8.27-8.07 (m, 3H), 7.97 (s, 1H), 7.79 (d, J=12.0Hz, 1H), 7.43 (dd, J=9.0, 4.8Hz, 2H), 7.35-7.26 (m, 2H), 7.05 (t, J=8.5Hz, 1H), 6.46 (d, J=5.2Hz, 1H), 4.46-4.18 (m, 3H), 3.03-2.82 (m, 2H), 2.30-2.12 (m, 2H), 2.07-1.89 (m, 2H), 1.88-1.76 (m, 2H) , 1.66-1.55 (m, 2H), 1.47 (s, 9H)

Compound 96 is dissolved in DCM, 5% TFA is added, is stirred to react 30min at room temperature, TLC tracking reaction is concentrated, column chromatographs to obtain product 42S after the reaction was completed.¹H NMR (DMSO, 300MHz): 9.72 (s of δ, 1H), 8.82 (d, J=5.5Hz, 1H), 8.45 (s, 1H), 8.25 (s, 1H), 8.08 (s, 1H), 7.88 (d, J=12.5Hz, 1H), 7.56 (dd, J=9.1, 4.8Hz, 2H), 7.51-7.35 (m, 2H), 7.07 (t, J=8.8Hz, 2H), 6.69 (d, J=5.4Hz, 1H), 4.73-4.60 (m, 1H), 3.68-3.50 (m, 2H), 3.27-3.18 (m, 2H), 2.48-2.22 (m, 4H), 1.69-1.54 (m , 4H) and

48 N- of embodiment (the fluoro- 4- of 3- ((7- (1- (- 4 alkyl of 1- isopropyl phenylpiperidines) -1 hydrogen-pyrazoles -4- alkyl) -1,6- benzodiazine -4- alkyl) oxygroup)-phenyl) and-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (43S) synthesis

Compound 42S is dissolved in acetonitrile, the lower cesium carbonate that 2eq is added is stirred at room temperature, the rear 2- iodopropane that 2eq is added dropwise is warming up at 85 DEG C and is stirred to react, and TLC tracking, addition EA is rushed dilute after the reaction was completed, with the Na of saturation₂CO₃Solution washing, saturation NaCl washing, anhydrous Na₂SO₄It is dry, it is concentrated under reduced pressure, column chromatographs to obtain target compound, yield 67%.¹H NMR(CD₃OD, 300MHz): 9.64 (s of δ, 1H), 8.64 (d, J=5.4Hz, 1H), 8.44 (s, 1H), 8.23 (s, 1H), 8.04 (s, 1H), 7.44-7.36 (m, 2H), 7.18 (t, J=8.7Hz, 2H), 7.03-6.96 (m, 1H), 6.89-6.81 (m, 2H), 6.25 (d, J=5.2Hz, 1H), 5.29-5.19 (m, 1H), 4.73-4.59 (m, 1H), 3.67-3.56 (m, 4H), 2.46-2.41 (m, 4H), 1.49 (m, 2H), 1.42-1.39 (m, 8H)

49 N- of embodiment (4- ((7- (3,5- dimethyl isoxazole -4- alkyl) -1,6- benzodiazine -4- alkyl) oxygroup) -3- fluorophenyl) and-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (45S) synthesis

Chloro- 1, the 6- benzodiazine (97) of the bromo- 4- of 7-

The synthesis of compound 97 same 53, starting material 2, the bromo- 4-aminopyridine of 6- bis-.¹H NMR (300MHz, CDCl₃) (d, J=4.7Hz, the 1H) of δ 9.40 (s, 1H), 8.93 (d, J=4.7Hz, 1H), 8.16 (s, 1H), 7.57

4- (chloro- 1, the 6- benzodiazine -7- alkyl of 4-) -3,5- dimethyl isoxazole (98)

The same 38S of the synthesis of compound 97, starting material 3,5- dimethyl isoxazole -4- pinacol borate, reaction temperature are 50 DEG C.¹H NMR (400MHz, DMSO) δ 9.68 (s, 1H), 9.09 (d, J=4.8Hz, 1H), 8.11 (s, 1H), 7.92 (d, J=4.7Hz, 1H), 2.67 (s, 3H), 2.47 (s, 3H)

N- (4- ((7- (3,5- dimethyl isoxazole -4- alkyl) -1,6- benzodiazine -4- alkyl) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (45S)

The same 1S of the synthesis of compound 45S, starting material are 98 and 26.¹H NMR (300MHz, CDCl₃) δ 10.28 (s, 1H), 9.83 (s, 1H), 8.81 (d, J=5.3Hz, 1H), 7.99 (s, 1H), 7.88 (s, 1H), 7.81 (d, J=12.4Hz, 1H), 7.53-7.37 (m, 2H), 7.28 (m, 2H), 7.06 (t, J=8.6Hz, 2H), 6.56 (d, J=5.2Hz, 1H), 2.67 (s, 3H), 2.52 (s, 3H), 1.83 (m, 2H), 1.60 (m, 2H)

50 N- of embodiment (the fluoro- 4- of 3- ((7- (pyridine -4- alkyl) -1,6- benzodiazine -4- alkyl) oxygroup)-phenyl) and-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (46S) synthesis

With compound 38S, initial feed is compound 1S and 4- pyridine boronic acid pinacol ester for the synthesis of compound 46S.¹H NMR (400MHz, DMSO): δ 10.39 (s, 1H), 9.92 (s, 1H), 8.89 (d, J=5.3Hz, 1H), 8.82 (s, 2H), 8.44 (s, 1H), 8.14 (d, J=4.5Hz, 2H), 7.86 (dd, J=12.1,2.2Hz, 1H), 7.54-7.43 (m, 2H), 7.39-7.30 (m, 2H), 7.17-7.04 (m, 2H), 6.65 (d, J=5.2Hz, 1H), 1.93-1.87 (m, 2H), 1.70-1.60 (m, 2H)

51 N- of embodiment (the fluoro- 4- of 3- ((7- (pyrimidine -5- alkyl) -1,6- benzodiazine -4- alkyl) oxygroup)-phenyl) and-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (47S) synthesis

With compound 38S, initial feed is which alcohol ester of compound 1S and pyrimidine -5- boric acid Knit-the-brows for the synthesis of compound 47S.¹H NMR (400MHz, DMSO): δ 10.46 (s, 1H), 10.03 (s, 1H), 9.88 (s, 1H), 9.67 (s, 2H), 9.32 (s, 1H), 8.97 (d, J=5.3Hz, 1H), 8.75 (s, 1H), 7.96 (d, J=13.5Hz, 1H), 7.65 (dd, J=9.1,5.1Hz, 2H), 7.61-7.51 (m, 2H), 7.17 (t, J=8.9Hz, 2H), 6.79 (d, J=5.4Hz, 1H), 1.53-1.44 (m, 4H)

52 N- of embodiment (the fluoro- 4- of 3- ((7- (4- nitrobenzophenone) -1,6- benzodiazine -4- alkyl) oxygroup)-phenyl) and-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (48S) synthesis

With compound 38S, initial feed is compound 1S and 4- nitrobenzene boronic acid pinacol ester for the synthesis of compound 48S.¹H NMR (400MHz, DMSO): δ 10.47 (s, 1H), 10.03 (s, 1H), 9.88 (s, 1H), 8.97 (d, J=5.3Hz, 1H), 8.69 (s, 1H), (8.62 s, 1H), 8.60 (s, 1H), (8.41 s, 1H), 8.39 (s, 1H), 7.97 (d, J=12.7Hz, 1H) 7.65 (dd, J=9.1,5.1Hz, 2H), 7.59-7.54 (m, 2H), 7.17 (t, J=8.9Hz, 2H), 6.79 (d, J=4.8Hz, 1H), 1.53-1.44 (m, 4H)

52 N- of embodiment (the fluoro- 4- of 3- ((7- (3,4- difluorophenyl) -1,6- benzodiazine -4- alkyl) oxygroup)-phenyl) and-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (49S) synthesis

With compound 38S, initial feed is compound 1S and 3,4- difluorobenzene pinacol borate for the synthesis of compound 49S.¹H NMR (400MHz, DMSO): δ 10.46 (s, 1H), 10.03 (s, 1H), 9.81 (s, 1H), 8.93 (d, J=6.4Hz, 1H), 8.58 (s, 1H), 8.44-8.34 (m, 1H), 8.23 (s, 1H), 7.96 (d, J=13.4Hz, 1H), 7.73-7.60 (m, 5H), 7.60-7.48 (m, 3H), 7.17 (t, J=8.7Hz, 2H), 6.74 (d, J=6.9Hz, 1H), 1.55-1.41 (m, 4H)

53 N- of embodiment (the fluoro- 4- of 3- ((7- (4- morpholine phenyl) -1,6- benzodiazine -4- alkyl) oxygroup)-phenyl) and-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (50S) synthesis

With compound 38S, initial feed is compound 1S and 4- morpholine phenyl boric acid pinacol ester for the synthesis of compound 50S.¹H NMR (400MHz, DMSO): 10.45 (s of δ, 1H), 10.03 (s, 1H), 9.74 (s, 1H), 8.86 (d, J=5.0Hz, 1H), 8.31 (s, 1H), 8.20 (d, J=8.5Hz, 2H), 7.95 (d, J=12.9Hz, 1H), 7.65 (dd, J=9.0, 5.0Hz, 2H), 7.58-7.50 (m, 2H), 7.16 (t, J=8.9Hz, 2H), 7.10 (d, J=8.5Hz, 2H), 6.64 (d, J=4.7Hz, 1H), 3.86-3.72 (m, 4H), 3.31-3.19 (m, 4H), 1.5 4-1.42 (m, 4H)

54 N- of embodiment (4- ((7- (isoxazole -4- alkyl) -1,6- benzodiazine -4- alkyl) oxygroup) -3- fluorophenyl) and-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (51S) synthesis

N- (4- ((bromo- 1, the 6- benzodiazine -4- alkyl of 7-) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (99)

The same 1S of the synthesis of compound 99, required raw material are bromo- 1, the 6- benzodiazine of the chloro- 7- of 4-.¹H NMR(CDCl₃, 300MHz): δ 10.32 (s, 1H), 9.56 (s, 1H), 8.81 (d, J=5.2Hz, 1H), 8.14 (s, 1H), 8.01 (s, 1H), 7.82 (d, J=11.6Hz, 1H), 7.54-7.39 (m, 2H), 7.35-7.27 (m, 1H), 7.07 (t, J=8.4Hz, 2H), 6.58 (d, J=5.1Hz, 1H), 1.91-1.79 (m, 2H), (1.35-1.17 m, 2H)

N- (4- ((7- (isoxazole -4- alkyl) -1,6- benzodiazine -4- alkyl) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (51S)

With compound 38S, initial feed is compound 99 and 4- isoxazole pinacol borate for the synthesis of compound 51S.¹H NMR (DMSO, 300MHz): δ 10.43 (s, 1H), 9.99 (s, 1H), 9.74 (s, 2H), 9.42 (s, 1H), 8.89 (d, J=5.3Hz, 1H), 8.40 (s, 1H), 7.93 (d, J=12.1Hz, 1H), 7.65-7.59 (m, 2H), 7.58-7.49 (m, 2H), 7.14 (t, J=8.9Hz, 2H), 6.69 (d, J=5.4Hz, 1H), (1.50-1.41 m, 4H)

55 N- of embodiment (4- ((7- (isothiazole -3- alkyl) -1,6- benzodiazine -4- alkyl) oxygroup) -3- fluorophenyl) and-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (52S) synthesis

With compound 38S, initial feed is compound 99 and 3- isothiazole pinacol borate for the synthesis of compound 52S.¹H NMR (DMSO, 300MHz): δ 10.46 (s, 1H), 10.03 (s, 1H), 9.77 (s, 1H), 8.95 (d, J=5.3Hz, 1H), 8.72 (d, J=1.7Hz, 1H), 8.66 (s, 1H), 8.32 (d, J=1.7Hz, 1H), 7.96 (d, J=13.7Hz, 1H) 7.66-7.62 (m, 2H), 7.58-7.52 (m, 2H), 7.17 (t, J=8.9Hz, 2H), 6.77 (d, J=5.0Hz, 1H), 1.48 (d, J=3.9Hz, 4H)

56 N- of embodiment (the fluoro- 4- of 3- ((7- (1- methyl-1 hydrogen-pyrazoles -4- alkyl) -1,6- benzodiazine -4- alkyl) oxygroup) phenyl) and -1- (4- fluorophenyl) -2- oxo -1,2- dihydropyridine -3- formamide (53S) synthesis

The same 45S of the synthesis of compound 53S, required raw material are bromo- 1, the 6- benzodiazine of the chloro- 7- of 4-.¹H NMR (300MHz, CDCl₃) 9.64 (s of δ, 1H), 9.10 (d, J=15.0Hz, 1H), 8.38 (d, J=21.8Hz, 1H), 8.30 (s, 1H), 8.22 (s, 1H), 7.96 (d, J=3.1Hz, 1H), 7.77 (d, J=3.1Hz, 1H), 7.61-7.57 (m, 1H), 7.58-7.55 (m, 1H), 7.56-7.52 (m, 1H), 7.45-7.36 (m, 2H), 7.25 (d, J=15.0Hz, 1H), 7.15 (dd, J=15.0, 3.0Hz, 1H), 6.86 (dd, J=15.0, 10.1Hz, 1H), 5.95 (d, J =21.8Hz, 1H), 3.94 (s, 3H)

Implement 57 N- (the fluoro- 4- of 3- ((7- (1- methyl-1 hydrogen-pyrazoles -4- alkyl) -1,6- benzodiazine -4- base) oxygroup) phenyl) and -5- (4- fluorophenyl) -4- oxo-Isosorbide-5-Nitrae-dihydropyridine -3- carbamide (54S) synthesis

The same 45S of the synthesis of compound 53S, required raw material are bromo- 1, the 6- benzodiazine of the chloro- 7- of 4-.¹H NMR (300MHz, CDCl₃) δ 9.64 (s, 1H), 9.49 (s, 1H), 9.10 (d, J=15.0Hz, 1H), 8.30 (s, 1H), 7.96 (d, J=3.1Hz, 1H), 7.93 (s, 1H), 7.71 (d, J=2.9Hz, 1H), 7.58 (dd, J=16.0,3.0Hz, 1H), 7.32-7.24 (m, 3H), 7.23 (s, 2H), 7.15 (dd, J=15.0,3.0Hz, 1H), 6.86 (dd, J=15.0,10.1Hz, 1H), 3.94 (s, 3H)

The synthesis of 58 N- of embodiment (4- ((3- chloropyridine [2,3-b] pyrazine -8- alkyl) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (55S)

The 33S of 200mg is dissolved in acetonitrile, the DIEA of 2eq is added, phosphorus oxychloride 0.5ml is instilled at room temperature, is stirred to react, TLC tracking, is extracted with ethyl acetate after the reaction was completed, successively uses sodium bicarbonate, saturated common salt washing, anhydrous sodium sulfate is dry, and concentration upper prop finally obtains product 55S, yield 80%.¹H NMR (400MHz, DMSO): δ 10.43 (s, 1H), 10.01 (s, 1H), 9.14 (s, 1H), 8.96 (d, J=5.1Hz, 1H), 7.93 (d, J=13.0Hz, 1H), 7.64 (dd, J=8.8,5.1Hz, 2H), 7.54 (d, J=9.1Hz, 1H), 7.45 (t, J=8.9Hz, 1H), 7.16 (t, J=8.9Hz, 2H), 7.03 (d, J=5.2Hz, 1H), 1.58-1.40 (m, 4H)；

Implement the synthesis of 59 N- (4- ((2- chloropyridine [2,3-b] pyrazine -8- alkyl) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (56S)

Operation same 55S, raw material 34S, yield 83%.¹H NMR (400MHz, DMSO): δ 10.44 (s, 1H), 10.01 (s, 1H), 9.24 (s, 1H), 8.96 (d, J=5.3Hz, 1H), 7.94 (dd, J=13.3,2.2Hz, 1H), 7.64 (dd, J=9.1,5.1Hz, 2H), 7.54 (d, J=8.9Hz, 1H), 7.46 (t, J=8.9Hz, 1H), 7.16 (t, J=8.9Hz, 2H), 7.03 (d, J=5.2Hz, 1H), 1.51-1.45 (m, 4H)；

Implement the synthesis of 60 N- (4- ((3- morpholine yl pyridines [2,3-b] pyrazine -8- alkyl) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (57S)

The 55S of 20mg is dissolved in tetrahydrofuran at room temperature, morpholine 0.5mL is added, is stirred to react at room temperature, TLC tracking, after the reaction was completed, ethyl acetate extraction, sodium bicarbonate, saturated common salt washing, anhydrous sodium sulfate is dry, and concentrated column obtains target compound.Yellowish solid product, yield 68%.¹H NMR (400MHz, DMSO): δ 10.38 (s, 1H), 10.01 (s, 1H), 8.86 (s, 1H), 8.60 (d, J=5.4Hz, 1H), 7.88 (d, J=13.1Hz, 1H), 7.64 (dd, J=9.0 5.0Hz, 2H), 7.49 (d, J=10.2Hz, 1H), 7.37 (t, J=9.0Hz, 1H), 7.16 (t, J=8.9Hz, 2H), 6.55 (d, J=5.4Hz, 1H), 3.84 (d, J=4.5Hz, 4H), 3.77 (d, J=4.6Hz, 4H), 1.47 (m, J=3.4Hz, 4H)；

Implement the synthesis of 61 N- (4- ((2- morpholine yl pyridines [2,3-b] pyrazine -8- alkyl) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (58S)

Operation same 57S, raw material 56S, yield 74%.¹H NMR (400MHz, DMSO): δ 10.34 (s, 1H), 10.02 (s, 1H), 9.00 (s, 1H), 8.51 (d, J=5.1Hz, 1H), 7.86 (dd, J=13.3,2.2Hz, 1H), 7.64 (dd, J=9.1,5.0Hz, 2H), 7.46 (d, J=8.7Hz, 1H), 7.32 (t, J=9.0Hz, 1H), 7.22-7.11 (m, 2H), 6.86 (d, J=5.1Hz, 1H), 3.8-3.63 (m, 8H), 1.52-1.42 (m, 4H)；

Implement 62 N- (the fluoro- 4- of 3- ((3- (4- methyl piperazine -1- alkyl) pyridine [2,3-b] pyrazine -8- alkyl) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (59S) synthesis

The same 57S of operation, raw material are 55S and N methyl piperazine, yield 44%.¹H NMR (400MHz, DMSO): δ 10.39 (s, 1H), 10.02 (s, 1H), 8.87 (s, 1H), 8.58 (d, J=5.3Hz, 1H), 7.89 (d, J=14.8Hz, 1H), 7.73-7.57 (m, 2H), 7.49 (d, J=10.1Hz, 1H), 7.36 (t, J=9.0Hz, 1H), 7.16 (t, J=8.8Hz, 2H), 6.53 (d, J=5.3Hz, 1H), 3.90-3.83 (m, 4H), 2.50-2.43 (m, 4H), 2.26 (s, 3H), 1.51-1.44 (m, 4H)；

Implement 63 N- (the fluoro- 4- of 3- ((3- (2- morpholine ethyoxyl base) pyridine [2,3-b] pyrazine -8- alkyl) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (60S) synthesis

The 2- morpholine ethanol of 4eq is added to tetrahydrofuran solution at room temperature, the potassium tert-butoxide of 1.5 dihydros is added afterwards, after being stirred to react 10min, the 55S of 1eq is added, continue to be stirred to react, TLC tracking, after the reaction was completed, EA extraction, saturated sodium bicarbonate is washed, saturated common salt washing, anhydrous sodium sulfate is dry, and column chromatographs to obtain product.Yellowish solid, yield 62%.¹H NMR (400MHz, DMSO): 10.41 (s of δ, 1H), 10.01 (s, 1H), 8.76 (d, J=5.5Hz, 1H), 8.71 (s, 1H), 7.91 (d, J=11.9Hz, 1H), 7.64 (dd, J=8.8, 5.0Hz, 2H), 7.51 (d, J=8.6Hz, 1H), 7.42 (t, J=9.0Hz, 1H), 7.16 (t, J=9.0Hz, 2H), 6.79 (d, J=5.2Hz, 1H), 4.63 (t, J=5.6Hz, 2H), 3.68-3.49 (m, 4H), 2.81 (t, J=7.3Hz, 2H), 2.56-2.5 1 (m, 4H), 1.56-1.39 (m, 4H)；

Implement 64 N- (the fluoro- 4- of 3- ((3- (3- morpholine propoxyl group base) pyridine [2,3-b] pyrazine -8- alkyl) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (61S) synthesis

The same 57S of operation, raw material are 55S and 3- morpholine propyl alcohol, yield 42%.¹H NMR (DMSO, 400MHz): 10.42 (s of δ, 1H), 10.02 (s, 1H), 8.75 (d, J=5.4Hz, 1H), 7.93 (d, J=13.4Hz, 1H), 7.69-7.61 (m, 2H), 7.54 (d, J=8.9Hz, 1H), 7.45 (t, J=8.9Hz, 1H), 7.16 (t, J=8.9Hz, 2H), 6.77 (d, J=5.3Hz, 1H), 4.58 (t, J=6.4Hz, 2H), 3.66-3.57 (m, 4H), 2.70-2.53 (m, 4H), 2.49-2.42 (m, 2H), 2.11-1.97 (m, 2H ), 1.54-1.41 (m, 4H)

Implement 65 N- (the fluoro- 4- of 3- ((3- ((3- morpholine propyl) amino) pyridine [2,3-b] pyrazine -8- alkyl) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (62S) synthesis

The 55S of 20mg and 100 μ L of N- (3- aminopropyl) morpholine are dissolved in tetrahydrofuran solution, are stirred to react at 60 DEG C of oil bath, TLC tracking, after the reaction was completed, EA is extracted, and saturated sodium bicarbonate is washed, saturated common salt washing, anhydrous sodium sulfate is dry, and column chromatographs to obtain product.White solid, yield 62%.1H NMR (400MHz, DMSO): 10.37 (s of δ, 1H), 10.01 (s, 1H), 8.50 (d, J=5.4Hz, 1H), 8.33 (s, 1H), 8.11 (t, J=6.2Hz, 1H), 7.88 (d, J=13.1Hz, 1H), 7.64 (dd, J=9.0, 5.0Hz, 2H), 7.48 (d, J=8.8Hz, 1H), 7.35 (t, J=9.0Hz, 1H), 7.16 (t, J=8.9Hz, 2H), 6.46 (d, J=5.2Hz, 1H), 3.68-3.54 (m, 4H), 3.47-3.42 (m, 2H), 2.44-2.30 ( M, 6H), 1.84-1.72 (m, 2H), 1.52-1.39 (m, 4H)；

Implement 66 N- (the fluoro- 4- of 3- ((2- ((3- morpholine propyl) amino) pyridine [2,3-b] pyrazine -8- alkyl) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (63S) synthesis

The same 62S of operation, raw material are 56S and N- (3- aminopropyl) morpholine, yield 66%.¹H NMR (DMSO, 400MHz): 10.34 (s of δ, 1H), 10.01 (s, 1H), 8.46 (s, 1H), 8.40 (d, J=5.3Hz, 1H), 7.98 (t, J=5.5Hz, 1H), 7.86 (d, J=13.8Hz, 1H), 7.68-7.58 (m, 2H), 7.44 (d, J=8.1Hz, 1H), 7.28 (t, J=9.1Hz, 1H), 7.16 (t, J=8.9Hz, 2H), 6.81 (d, J=5.0Hz, 1H), 3.55-3.47 (m, 6H), 2.44-2.25 (m, 6H), 1.76-1.63 (m, 2H), 1.5 4-1.42 (m, 4H)；

Implement the synthesis of 67 N- (4- ((2- piperazinyl pyridine [2,3-b] pyrazine -8- alkyl) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (64S)

The same 62S of operation, raw material are 56S and piperazine, yield 45%.¹H NMR (400MHz, CDCl₃): δ 8.61 (s, 1H), 8.57 (d, J=5.6Hz, 1H), 7.75 (d, J=12.3Hz, 1H), 7.49-7.43 (m, 2H), 7.27-7.21 (m, 2H), 7.05-7.00 (m, 2H), 6.46 (d, J=3.4Hz, 2H), 3.95-3.89 (m, 4H), 3.11-2.95 (m, 4H), 1.71-1.62 (m, 4H)；

Implement the synthesis of 68 N- (4- ((2- piperazinyl pyridine [2,3-b] pyrazine -8- alkyl) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (65S)

The same 62S of operation, raw material are 56S and piperazine, yield 48%.¹H NMR (400MHz, DMSO): δ 10.33 (s, 1H), 10.01 (s, 1H), 8.97 (s, 1H), 8.48 (d, J=5.1Hz, 1H), 7.85 (d, J=13.2Hz, 1H), 7.64 (dd, J=9.1,5.1Hz, 2H), 7.45 (d, J=8.5Hz, 1H), 7.30 (t, J=9.1Hz, 1H), 7.15 (t, J=8.9Hz, 2H), 6.85 (d, J=5.1Hz, 1H), 3.73-3.63 (m, 4H), 2.86-2.77 (m, 4H), 1.50-1.44 (m, 4H)；

Implement 69 N- (the fluoro- 4- of 3- ((2- (2- (4- methyl piperazine -1- alkyl) ethyoxyl) pyridine [2,3-b] pyrazine -8- alkyl) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (66S) synthesis

The same 57S of operation, raw material are 56S and 1- ethoxy -4- methyl piperazine, yield 63%.¹H NMR (400MHz, DMSO): 10.73 (s of δ, 1H), 10.35 (s, 1H), 9.15 (s, 1H), 9.06 (d, J=5.2Hz, 1H), 8.23 (d, J=12.9Hz, 1H), 8.03-7.92 (m, 2H), 7.87-7.79 (m, 1H), 7.69 (t, J=9.0Hz, 1H), 7.49 (t, J=8.7Hz, 2H), 7.33 (d, J=5.2Hz, 1H), 4.84 (t, J=5.4Hz, 2H), 3.67 (s, 4H), 3.05 (t, J=5.7Hz, 2H), 2.90-2.76 (m, 7H), 1.90-1.7 2 (m, 4H)

Implement 70 N- (the fluoro- 4- of 3- ((2- (2- morpholine ethyoxyl) pyridine [2,3-b] pyrazine -8- alkyl) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (67S) synthesis

The same 57S of operation, raw material are 56S and 2- morpholine ethanol, yield 68%.¹H NMR (400MHz, DMSO): δ 10.40 (s, 1H), 10.02 (s, 1H), 8.84 (s, 1H), 8.75 (d, J=5.0Hz, 1H), 7.91 (d, J=12.6Hz, 1H), 7.73-7.60 (m, 2H), 7.50 (d, J=9.5Hz, 1H), 7.37 (t, J=9.8Hz, 1H), 7.17 (t, J=9.5Hz, 2H), 7.01 (d, J=4.3Hz, 1H), 4.64-4.46 (m, 2H), 3.68-3.46 (m, 4H), (2.84-2.66 m, 2H), 2.60-2.33 (m, 4H), 1.60-1.41 (m, 4H)；

Implement 71 N- (the fluoro- 4- of 3- ((2- (3- morpholine propoxyl group) pyridine [2,3-b] pyrazine -8- alkyl) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diamides (68S) synthesis

The same 57S of operation, raw material are 56S and 3- morpholine propyl alcohol, yield 64%.¹H NMR (400MHz, DMSO): 10.40 (s of δ, 1H), 10.02 (s, 1H), 8.81 (s, 1H), 8.76-8.64 (m, 1H), 7.91 (d, J=13.0Hz, 1H), 7.72-7.56 (m, 2H), 7.51 (d, J=8.7Hz, 1H), 7.39 (t, J=9.1Hz, 1H), 7.17 (t, J=7.6Hz, 2H), 6.97 (d, J=4.7Hz, 1H), 4.48 (t, J=7.1Hz, 2H), 3.64-3.46 (m, 4H), 2.50-2.26 (m, 6H), 1.98 (t, J=9.1Hz, 2H), 1.5 9-1.40 (m, 4H)

EXPERIMENTAL EXAMPLE

EXPERIMENTAL EXAMPLE 1: inhibiting effect of the pyrido nitrogen heterocyclic to c-Met kinases

Receptor tyrosine kinase c-Met molecular level enzyme activity inhibits preliminary assessment experiment

1, test method

By enzyme reaction substrate Poly (Glu, Tyr)_4∶120 μ g/ml are diluted to the PBS (10mM sodium phosphate buffer, 150mM NaCl, pH7.2-7.4) of no potassium ion, 125 hole μ L/ coated elisa plates set 37 DEG C of reactions 12-16 hours.Board-washing after liquid is discarded in hole, three times with T-PBS (PBS containing the 0.1%Tween-20) board-washing in 200 holes μ L/, 5 minutes every time.It is ELISA Plate 1-2 hours dry in 37 DEG C of baking ovens.

Every hole, which is added, uses reaction buffer (50mM 4- hydroxyethyl piperazineethanesulfonic acid (HEPES) pH 7.4,50mM MgCl₂, 0.5mM MnCl₂, 0.2mM Na₃VO₄, 1mM dithiothreitol (DTT) (DTT)) and diluted 50 μ L of atriphos (ATP) solution, 5 μM of final concentration.Compound is diluted to suitable concentration with dimethyl sulfoxide (DMSO), 1 hole μ L/ or or the DMSO (negative control hole) containing respective concentration, it adds and is reacted with the diluted c-Met kinase domain recombinant protein starting of 49 μ L reaction buffers, experiment need to set no two hole of ATP control wells every time.37 DEG C of shaking tables (100rpm) are set to react 1 hour.T-PBS board-washing is three times.100 hole μ L/ of primary antibody PY99 dilution is added, 37 DEG C of shaking tables react 0.5 hour.T-PBS board-washing is three times.100 hole μ L/ of IgG dilution of secondary antibody horseradish peroxidase-labeled sheep anti mouse is added, 37 DEG C of shaking tables react 0.5 hour.T-PBS board-washing is three times.100 hole μ L/ of o-phenylenediamine (OPD) developing solution of 2mg/ml is added (with containing 0.03%H₂O₂0.1M citric acid-sodium citrate buffer solution (pH=5.4) dilution), 25 DEG C are protected from light 1-10 minutes.(ultrasound need to be used when OPD dissolves, developing solution needs ready-to-use).2M H is added₂SO₄50 hole μ L/ stopped reactions, use is adjustable Wavelength type microwell plate microplate reader SPECTRA MAX 190 is read, wavelength 490nm.

The inhibiting rate of sample is acquired by following equation:

(compound is 10 for the compound with effectively inhibition c-Met kinase activity that above-mentioned screening is obtained^-5Inhibiting rate > 50% of the M to receptor tyrosine kinase c-Met) it is made into gradient concentration, carry out IC₅₀Evaluation.The IC that each compound molecule level inhibits protein tyrosine kinase is calculated with four parametric methods₅₀Acquired results classification is included in the following table 1 by value according to its concentration range:

Inhibitory activity of 1 the compound of the present invention of table to c-Met kinases and its inhibitory activity to the c-Met EBC-1 cell Proliferation mediated

^aTest compound inhibits c-Met kinase activity.A:1nM < IC₅₀< 10nM；B:10nM < IC₅₀< 100nM；C:100nM < IC₅₀1 μM of <；D:1 μM of < IC₅₀10 μM of <；ND: it does not test.

As a result: research finds that multiple the compounds of this invention have different degrees of inhibitory activity to c-Met kinases, and part of compounds has very strong inhibiting effect to c-Met kinases under 10nM concentration, and 503nhibiting concentration is 1nM < IC₅₀< 10nM.Prompt the compound of the present invention, which has, efficiently acts on c-Met kinases, is the c-Met kinase inhibitor of structure novel.

EXPERIMENTAL EXAMPLE 2: influence of the compounds of this invention to the c-Met cell strain proliferative capacity mediated

To non-small cell cancer cell EBC-1 cell, (MET gene magnification leads to Met continuous activation cell strain to compound, for Met dependent tumors cell strain) growth inhibition detection use sulphonyl rhodamine B (sulforhodamine B, SRB) decoration method.Inoculation certain amount is in the EBC-1 cell of logarithmic growth phase in 96 well culture plates, every 90 μ L of hole, and the compound or solvent control of 10 μ L various concentrations, each 3 multiple holes of concentration are separately added into after overnight incubation.After compound effects 72 hours, after effect, attached cell removes culture solution, 10% (w/v) trichloroacetic acid (100 hole μ L/) is added in 4 DEG C of fixed 1hr, then use distilled water flushing five times, after being dried at room temperature for, SRB solution (4mg/mL is added in every hole, it is dissolved in 1% glacial acetic acid) 100 μ L, it after being incubated for dyeing 15min at room temperature, is rinsed five times with 1% glacial acetic acid and washes away unbonded SRB, after drying at room temperature, the optical density (OD value) under 100 μ L, VERSMax microplate reader of 10mM Tris solution measurement 515nm wavelength is added in every hole.By the inhibiting rate for calculating compound on tumor cell growth with following equation: inhibiting rate (%)=(OD control wells-OD dosing holes)/OD control wells × 100%.Experiment is repeated twice.IC₅₀Data extrapolate range according to the test result that concentration is arranged in primary dcreening operation.

As a result: multiple compounds of the invention EBC-1 cell Proliferation highly expressed to c-Met kinases has apparent inhibition to make With, show the compound be able to suppress by c-Met activation mediate cell-proliferation activity.Specific data see the above table 1, and ND expression does not carry out dependence test, no related data in table.

EXPERIMENTAL EXAMPLE 3: inhibiting effect of the compound 7S to multiple protein kinases

For experimental method with EXPERIMENTAL EXAMPLE 1, experimental result is as shown in table 2.

Inhibiting rate (%) of the 2. compound 7S of table to tyrosine kinase activity

As can be seen from the above table, the compound of the present invention 7S shows the inhibitory activity to a variety of kinases such as c-Met, Flt-1, PDGFR- α, PDGFR- β, RET, c-Src, EPH-A2, is the multiple kinase inhibitor an of new construction.

EXPERIMENTAL EXAMPLE 4: compound 7S and 8S tests big raticide for pharmacokinetics

1. dosage regimen

SD rat 14, male, weight 200-220g, 4 groups are randomly divided into, every group 4/3, stomach-filling and vein give 7S and 8S respectively, compound is dissolved in the physiological saline of 5% DMSO, and 5% tween-80 (Tween 80) hydrotropy is added, and final sample concentration is 1mg/ml.Specific arrangement see the table below 3:

The 3 big raticide of compound 7S and 8S of table tests dosage regimen for pharmacokinetics

Fasting 12h, free water before testing.2h is unified after administration feeds.

2. blood sampling time point and sample treatment:

Gastric infusion: 0.25,0.5,1.0,2.0,3.0,4.0,6.0,8.0 and for 24 hours after administration；

Intravenously administrable: 5min, 0.25,0.5,1.0,2.0,4.0,6.0,8.0 and for 24 hours after administration；

It in the above setting time point through rat eye rear vein beard extracting vein blood 0.3ml, sets in heparinised tubes, 11000rpm is centrifuged 5min, and separated plasma freezes in -20 DEG C of refrigerators.

3. sample test and data analysis

Using the concentration of compound in LC/MS/MS method measurement rat plasma.

The pharmacokinetic parameter after administration is calculated using the non-compartment model of 1.3 software of Phoenix (Pharsight company, the U.S.).

Up to Cmax C_maxWith peak time T_maxFor measured value；

Area under the drug-time curve AUC0-t value: it is calculated using trapezoidal method；AUC_0-∞=AUC_0-t+C_t/ ke, Ct are that the last one can measure the blood concentration at time point, k_eFor elimination rate constant；

Eliminate half-life period t_1/2=0.693/ke；

Mean residence time MRT=AUMC/AUC.

Clearance rate CL=D/AUC_0-∞；

Vdss V_ss=CL × MRT

Absolute bioavailability F=(AUC stomach-filling × D vein)/(AUC vein × D stomach-filling) × 100%

See Table 4 for details and table 5 for experimental data.

The pharmacokinetic parameters of table 4, rat intravenous injection 5mg/kg compound 7S and 8S

The pharmacokinetic parameters of table 5, rat oral gavage 10mg/kg compound 7S and 8S

The results show that compound 7S shows good medicine for property: bioavilability F=51.8%, mean residence time MRT=2.6h, half-life period t_1/2=1.66h, area AUC=16652h*ng/ml when medicine.

EXPERIMENTAL EXAMPLE 5: growth inhibition effect of the compound 7S to human lung cancer EBC-1 nude mouse subcutaneous transplantation tumor

Experimental method

EBC-1 cell presses 5 × 10⁶/ armpit on the right side of nude mouse is only inoculated respectively, it is formed after transplantable tumor after passing three generations in nude mice again and is used.The tumor tissues of growth animated period are taken, cut into 1.5mm under aseptic condition³It is subcutaneous to be inoculated in armpit on the right side of nude mouse for left and right.Transplantable tumor diameter is measured with vernier caliper, nude mouse subcutaneous transplantation tumor vernier caliper measurement transplantable tumor diameter grows to 120-130mm to tumor average volume³Animal is grouped by left and right at random.7S, 100mg/kg and 10mg/kg group, once a day oral administration, successive administration 21 days (qd/21, po).Positive control medicine PF2341066 50mg/kg, once a day oral administration, successive administration 21 days.Solvent control gives equivalent solvent.In whole experiment process, transplantable tumor diameter is measured 2 times a week, while weighing mouse weight.The calculation formula of gross tumor volume (tumor volume, TV) are as follows: TV=1/2 × a × b², wherein a, b respectively indicate length and width.Relative tumour volume (relative tumor volume, RTV), calculation formula are as follows: RTV=V are calculated according to the result of measurement_t/V₀.Wherein V₀(d when for sub-cage administration₀) measurement gained gross tumor volume, V_tGross tumor volume when to measure each time.The evaluation index of anti-tumor activity is 1) Relative tumor proliferation rate T/C (%), and calculation formula is as follows: T/C (%)=(T_RTV/C_RTV) × 100%, T_RTV: treatment group RTV；C_RTV: negative control group RTV；2) gross tumor volume growth inhibition rate GI%, calculation formula are as follows: GI%=[1- (TVt-TV₀)/(CVt-CV₀)] × 100%, TVt be treatment group measure every time knurl product；TV₀Gained knurl product when for treatment group's sub-cage administration；CVt is the knurl product that control group measures every time；CV₀Gained knurl product when for control group sub-cage administration；3) tumor-like hyperplasia, calculation formula are as follows: tumor-like hyperplasia %=(Wc-W_T)/Wc × 100%, Wc: control group knurl weight, W_T: treatment group's knurl weight.

Experimental result: as shown in Fig. 1 and table 6, compound 7S 100mg/kg group, once a day oral administration, successive administration 21 days, there is highly significant inhibiting effect to the growth of human lung cancer EBC-1 nude mouse subcutaneous transplantation tumor, is 9.58% in the 21st day gained T/C percentage.Compound 7S 10mg/kg group, once a day oral administration successive administration 21 days, have certain inhibiting effect to the growth of human lung cancer EBC-1 nude mouse subcutaneous transplantation tumor, are 46.24% in the 21st day gained T/C percentage.Positive control medicine PF2341066 50mg/kg group, once a day oral administration successive administration 21 days, have highly significant inhibiting effect to EBC-1 nude mouse subcutaneous transplantation tumor, and all mouse tumors subside completely within the 21st day, and gained T/C percentage is 0.00%.Each administration group mouse state is good during administration, no dead mouse.

6. 7S of table acts on the experimental therapy of human lung cancer EBC-1 nude mouse subcutaneous transplantation tumor

^*P < 0.001 is tumor regression number of mice in " () "

Claims

A kind of pyrido nitrogen heterocyclic with structure shown in following general formula I, its isomers and pharmaceutically acceptable salt or pharmaceutically acceptable solvate,

Wherein,

Indicate singly-bound or double bond；

R¹And R²It is each independently selected from hydrogen and halogen；

X is not present or X and Y is each independently selected from C, N, O and S；

N is 0,1,2 or 3；M is 0 or 1；

R³It is not present or for hydrogen, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₆-C₁₀Aryl, substituted or unsubstituted heteroatomic five yuan containing 1-2 in N, O, S or hexa-atomic saturation or unsaturated heterocycle group, substituted or unsubstituted heteroatomic five yuan containing 1-2 in N, O, S or hexa-atomic saturation or unsaturated heterocycle base carbonyl,Or substituted or unsubstituted heteroatomic five yuan or six-membered Hetero-aromatic group for containing 1-2 in N, O, S, wherein the substituent group for 1 or 2 and can be each independently selected from halogen ,-CN ,-CF₃、-NO₂, hydroxyl, C₁-C₆Alkyl, C₁-C₆Alkyl-substituted amido, C₁-C₆The C that alkoxy, benzyl, halogen replace₁-C₆Alkoxy, C₁-C₆Alkyl sulphonyl and unsubstituted or C₁-C₆Alkyl-substituted heteroatomic five yuan containing 1-2 in N and O or hexa-atomic saturation or unsaturated heterocycle base or heteroaryl ring group；

R⁶It is not present or selected from hydrogen and C₁-C₆Alkyl；

R⁷It is not present or selected from hydrogen and C₁-C₆Alkyl；

Z is amino, phenylacetyl amido or following any structure:

In above-mentioned general formula II, III, IV, V, R⁴Selected from hydrogen, C₁-C₆Alkyl and C₅-C₁₀Aryl or heteroaryl；R⁵And R^5′It is each independently selected from hydrogen, halogen and C₁-C₆Alkoxy；

Ring B is containing 1 or 2 heteroatomic five yuan in N, O, S or hexa-atomic saturation or unsaturated heterocycle group or miscellaneous aromatic group.
Compound, its isomers and pharmaceutically acceptable salt according to claim 1 or pharmaceutically acceptable solvate, wherein

R¹And R²It is each independently selected from hydrogen, F, Cl and Br；

X is not present or X and Y is each independently selected from C, N and O；

N is 0,1 or 2；M is 0 or 1；

R³It is not present or for hydrogen, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₆-C₁₀Aryl, substituted or unsubstituted heteroatomic five yuan containing 1-2 in N, O, S or hexa-atomic saturation or unsaturated heterocycle group, substituted or unsubstituted heteroatomic five yuan containing 1-2 in N, O, S or hexa-atomic saturation or unsaturated heterocycle base carbonyl,Or substituted or unsubstituted heteroatomic five yuan or six-membered Hetero-aromatic group for containing 1-2 in N and O, wherein the substituent group for 1 or 2 and can be each independently selected from halogen ,-CN, benzyl ,-NO₂、C₁-C₆Alkyl, C₁-C₆Alkyl-substituted amido, C₁-C₆Alkyl sulphonyl and unsubstituted or C₁-C₆Alkyl-substituted heteroatomic five yuan containing 1-2 in N and O or hexa-atomic saturation or unsaturated heterocycle group；

R⁶It is not present or selected from hydrogen and C₁-C₄Alkyl；

R⁷It is not present or selected from hydrogen, methyl, ethyl and propyl；

R⁴Selected from hydrogen and C₁-C₆Alkyl；R⁵And R^5′It is each independently selected from hydrogen, F, Cl, Br and C₁-C₄Alkoxy；

Ring B is containing 1 or 2 heteroatomic five yuan in N or O or hexa-atomic saturation or unsaturated heterocycle group or miscellaneous aromatic group.
Compound, its isomers and pharmaceutically acceptable salt according to claim 1 or 2 or pharmaceutically acceptable solvate, wherein

R¹Selected from hydrogen, Cl and Br；R²Selected from hydrogen, F and Cl；

X is not present or X and Y is each independently selected from C, N and O；

N is 0,1 or 2；M is 0 or 1；

R³It is not present or for hydrogen, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₆-C₁₀Aryl, substituted or unsubstituted heteroatomic five yuan containing 1-2 in N, O, S or hexa-atomic saturation or unsaturated heterocycle group, substituted or unsubstituted heteroatomic five yuan containing 1-2 in N, O, S or hexa-atomic saturation or unsaturated heterocycle base carbonyl,Or substituted or unsubstituted heteroatomic five yuan or six-membered Hetero-aromatic group for containing 1-2 in N and O, wherein the substituent group for 1 or 2 and can be each independently selected from halogen ,-NO₂, benzyl, C₁-C₄Alkyl, C₁The alkyl-substituted amido of-C4, C₁-C₄Alkyl sulphonyl and unsubstituted or C₁-C₆Alkyl-substituted heteroatomic five yuan containing 1-2 in N and O or hexa-atomic saturation or unsaturated heterocycle group；

R⁶It is not present or selected from hydrogen and C₁-C₂Alkyl；

R⁷It is not present or for methyl；

R⁴Selected from hydrogen and C₁-C₃Alkyl；Preferably, R⁴For hydrogen or methyl；

R⁵And R^5′It is each independently selected from hydrogen, F and C₁-C₂Alkoxy；；

Ring B is five yuan containing 1 or 2 N atom or hexa-atomic saturation or unsaturated heterocycle group or miscellaneous aromatic group.
Compound, its isomers and pharmaceutically acceptable salt according to claim 1 to 3 or pharmaceutically acceptable solvate, wherein

R¹For hydrogen, Cl or Br；R₂For hydrogen or F；

X is not present or X and Y is each independently selected from C, N and O；

N is 0,1 or 2；M is 0 or 1；

R³It is not present or for C₁-C₃Alkyl, substituted or unsubstituted pyridyl group, substituted or unsubstituted morpholinyl, substituted or unsubstituted morpholinyl carbonyl,Substituted or unsubstituted piperidyl, substituted or unsubstituted imidazole radicals, substituted or unsubstituted piperazinyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted pyrimidine radicals, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted phenyl or substituted or unsubstituted pyrazolyl, wherein, the substituent group can be 1 or 2 and be each independently selected from F, Cl, Br ,-NO₂, benzyl, C₁-C₃Alkyl, C₁The alkyl-substituted amido of-C3, C₁-C₃Alkyl sulphonyl, it is unsubstituted or C₁-C₆Alkyl-substituted piperidyl and morpholinyl；

R⁶It is not present or for hydrogen or methyl；

R⁷It is not present or for methyl；

Z is amino, phenylacetyl amido or following any structure:

Ring B is with pyridine or together with X-shaped at structure shown in one of following skeleton symbol:
Compound described in any one of -4, its isomers and pharmaceutically acceptable salt or pharmaceutically acceptable solvate according to claim 1, wherein the compound is selected from one of following compounds compound:
The preparation method of compound according to claim 1-5, its isomers, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate, this method is as shown in one of following reaction scheme:

Reaction scheme one:

Wherein, R⁸ForR⁹ForY、R²、R³、R⁷, the definition of Z, m and n it is identical with claim 1-5；

(1) compound 5 is obtained by compound 4 through chlorination, and chlorinating agent is thionyl chloride (SOCl₂)/N, N- dimethyl ammonium formate (DMF), phosphorus oxychloride (POCl₃)/DMF or POCl₃/ n,N-diisopropylethylamine (DIEA)/acetonitrile (MeCN) etc., preferably POCl₃/DMF；

(2) compound 6 is obtained by the deprotection of compound 5, deprotects reagent are as follows: Boron tribromide (BBr₃)/methylene chloride (DCM), 40% hydrogen bromide (HBr) aqueous solution, pyridine hydrochloride, hydrochloric acid or sulfuric acid, hydrochloric acid-aluminium chloride, aluminium chloride-ethyl mercaptan, trim,ethylchlorosilane (TMSCl)/sodium iodide (NaI), trifluoromethanesulfonic acid, preferably trifluoromethanesulfonic acid；

(3) compound 6 is reacted through Mitsunobu generates compound 7, and selected reagent is diethyl azodiformate (DEAD)/triphenylphosphine (PPh₃), N ',-three fourth phosphine TBP of N '-tetra isopropyl azodicarboxy amide (TIPA), 1,1 '-(azo-2-carboxylic acid) two piperidines (ADDP)-TBP, tetramethyl azoformic acid ammonium (TMAD)-TBP, 4,7- dimethyl -3,4,5,6,7,8- hexahydro -1,2,4,7- tetra- azepine Xin Yin -3,8- diketone (DHTD)-TBP, cyanomethylene tri-n-butyl phosphine (CMBP) or cyano methylene Base trimethyl-phosphine (CMMP), preferably DEAD/PPh₃；

(4) 7 nucleo philic substitution reaction of compound generates compound 8, and selected reagent is common organic base or inorganic base, such as Anhydrous potassium carbonate, cesium carbonate, triethylamine (TEA), DIEA, potassium tert-butoxide, sodium hydride, sodium methoxide, sodium ethoxide；Preferably Anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium tert-butoxide；

(5) compound 8 obtains compound 9, preferred reaction conditions through debrominate are as follows: palladium carbon (Pd/C)-ammonium formate, Pd/C- acetamide, Pd/C- hydrogen；Preferably Pd/C- ammonium formate；

Reaction scheme two:

Wherein, R⁸ForR⁹ForY、R²、R³、R⁷, the definition of Z, m and n it is identical as claim 1-5 respectively；

(1) 5 debrominate of compound obtains compound 10, preferred reaction conditions are as follows: Pd/C- ammonium formate, Pd/C- acetamide, Pd/C- hydrogen；Preferably Pd/C- ammonium formate；

(2) compound 11 is obtained by the deprotection of compound 10；Deprotect reagent are as follows: BBr₃/ DCM, 40%HBr aqueous solution, pyridine hydrochloride, hydrochloric acid or sulfuric acid, hydrochloric acid-aluminium chloride, aluminium chloride-ethyl mercaptan, TMSCl/NaI, trifluoromethanesulfonic acid, preferably trifluoromethanesulfonic acid；

(3) compound 11 is reacted through Mitsunobu generates compound 12, and selected reagent is DEAD/PPh₃, TIPA-TBP, ADDP-TBP, TMAD-TBP, DHTD-TBP, CMBP or CMMP；Preferably DEAD/PPh₃；

(4) 12 nucleo philic substitution reaction of compound generates compound 9, and selected reagent is common organic base or inorganic base, such as Anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium tert-butoxide, sodium hydride, sodium methoxide, sodium ethoxide；Preferably Anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium tert-butoxide；

Reaction scheme three:

Wherein, R¹⁰ForR⁹ForX、Y、R²、R³、R⁶、R⁷, the definition of Z, m and n it is identical as claim 1-5 respectively；X ' is Cl or Br；

(1) compound 14 is dechlorinated obtains compound 15, and reaction reagent is zinc (Zn)/acetic acid (MeCOOH)；

(2) compound 16 obtains compound 17, chlorinating agent SOCl through chlorination₂/DMF、POCl₃/DMF、POCl₃/ DIEA/MeCN etc., preferably POCl₃/DIEA/MeCN；

(3) 17 nucleo philic substitution reaction of compound generates compound 18, and selected reagent is common organic base or inorganic base, such as Anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium tert-butoxide, sodium hydride, sodium methoxide, sodium ethoxide；Preferably Anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium tert-butoxide；

Reaction scheme four:

Wherein, R¹⁰ForR⁹ForX、Y、R²、R³、R⁶、R⁷, the definition of Z, m and n it is identical as claim 1-5 respectively；X ' is Cl or Br；

(1) compound 15 obtains compound 15I, chlorinating agent SOCl through chlorination₂/DMF、POCl₃/DMF、 POCl₃/ DIEA/MeCN etc., preferably POCl₃/DIEA/MeCN；

(2) compound 15I nucleo philic substitution reaction generates compound 15II, and selected reagent is common organic base or inorganic base, such as Anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium tert-butoxide, sodium hydride, sodium methoxide, sodium ethoxide；Preferably Anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium tert-butoxide；

(3) compound 15II generates compound 18 through Suzuki coupling reaction, and alkali used is potassium acetate, potassium phosphate or potassium carbonate；Solvent for use is dimethyl sulfoxide, DMF, dioxane or toluene, and suitable water is added；Catalyst used is tetra-triphenylphosphine palladium, 1,1 '-bis- Diphenyl phosphino ferrocene palladium chloride PdCl₂(dppf)；

Reaction scheme five:

Wherein, R¹⁰ForR⁹ForX、Y、R²、R³、R⁶、R⁷, the definition of Z, m and n it is identical as claim 1-5 respectively；

(1) substitution reaction generates compound 19, and selected reagent is common organic base or inorganic base, such as Anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium tert-butoxide, sodium hydride, sodium methoxide, sodium ethoxide；Preferably Anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium tert-butoxide；

(2) compound 19 obtains compound 20 through reduction, and go back original reagent used is nickel chloride (NiCl₂)/sodium borohydride (NaBH₄)、Zn/AcOH、Pd/C-H₂, Fe/ hydrogen chloride (HCl), vulcanized sodium (Na₂S)/ethyl alcohol (EtOH), ammonium hydro sulfide (NH₄HS), lithium aluminium hydride reduction (LiAlH₄)；Preferably NiCl₂/NaBH₄、Pd/C-H₂；

(3) compound 20 obtains compound 21 and 22 through cyclization, and cyclization condition is aldehyde radical ethyl acetate, and solvent is various Conventional solvents, such as methanol (MeOH), EtOH, acetonitrile (MeCN), dioxane etc.；

(4) chlorination, chlorinating agent SOCl₂/DMF、POCl₃/DMF、POCl₃/ DIEA/MeCN etc., Preferably POCl₃/DIEA/MeCN；

(5) nucleophilic substitution, selected reagent are common organic base or inorganic base, such as Anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium tert-butoxide, sodium hydride, sodium methoxide, sodium ethoxide；Preferably Anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium tert-butoxide.
The composition selected from one of compound described in any one of claim 1-5 or multiple compounds, its isomers, pharmaceutically acceptable salt or pharmaceutically acceptable solvate comprising therapeutically effective amount.
Composition described in compound described in any one of claim 1-5, its isomers, pharmaceutically acceptable salt, pharmaceutically acceptable solvate and its claim 7 is preparing the application in the drug as multiple target point kinases inhibitor；In preparation for inhibiting the application in the active drug of tyrosine kinase c-Met；Application in drug of the preparation for preventing or treating abnormal cell proliferation relevant to biological intracorporal hepatocyte growth factor receptor (c-Met), metamorphosis and the relevant disease of hypoerkinesia and disease relevant with angiogenesis or metastases；Application in preparation prevention or treatment tumour growth and the drug of transfer；

Wherein, the kinases includes c-Met, Flt-1, PDGFR- α, PDGFR- β, RET, c-Src, EPH-A2, FGFR, Abl, Lck, KDR, IGF-1 α and ALK.
Application according to claim 8, wherein the tumour is lung cancer, thyroid gland encephaloid, glioblastoma, gastric cancer, clear-cell carcinoma, breast cancer, oophoroma, prostate cancer or colorectal cancer.